Pyrimidine derivatives for the treatment of abnormal cell growth

ABSTRACT

The present invention relates to a compound of the formula 1 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1 -R 4  are as defined herein. Such novel pyrimidine derivatives are useful in the treatment of abnormal cell growth, such as cancer, in mammals. This invention also relates to a method of using such compounds in the treatment of abnormal cell growth in mammals, especially humans, and to pharmaceutical compositions containing such compounds.

CROSS-REFERENCE TO RELATED APPLICATION

This patent application is a continuation of U.S. patent applicationSer. No. 12/059,889, filed Mar. 31, 2008, which is a continuation U.S.patent application Ser. No. 11/506,689, filed Aug. 17, 2006, now U.S.Pat. No. 7,351,712, which is a continuation of U.S. patent applicationSer. No. 10/733,215, filed Dec. 11, 2003, now U.S. Pat. No. 7,109,335,which claims the benefit of priority to U.S. Provisional PatentApplication Ser. No. 60/500,742, filed Sep. 5, 2003 and U.S. ProvisionalPatent Application Ser. No. 60/435,670, filed Dec. 20, 2002.

BACKGROUND OF THE INVENTION

This invention relates to novel pyrimidine derivatives that are usefulin the treatment of abnormal cell growth, such as cancer, in mammals.This invention also relates to a method of using such compounds in thetreatment of abnormal cell growth in mammals, especially humans, and topharmaceutical compositions containing such compounds.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e., a genewhich, on activation, leads to the formation of malignant tumor cells).Many oncogenes encode proteins that are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are enzymes which span the cell membrane andpossess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion which functions as a kinase to phosphorylate specific tyrosineresidues in proteins and hence to influence cell proliferation. Otherreceptor tyrosine kinases include c-erbB-2, c-met, tie-2, PDGFr, FGFr,and VEGFR. It is known that such kinases are frequently aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. It has also beenshown that epidermal growth factor receptor (EGFR), which possessestyrosine kinase activity, is mutated and/or overexpressed in many humancancers such as brain, lung, squamous cell, bladder, gastric, breast,head and neck, oesophageal, gynecological and thyroid tumors.

Accordingly, it has been recognized that inhibitors of receptor tyrosinekinases are useful as selective inhibitors of the growth of mammaliancancer cells. For example, erbstatin, a tyrosine kinase inhibitor,selectively attenuates the growth in athymic nude mice of a transplantedhuman mammary carcinoma that expresses epidermal growth factor receptortyrosine kinase (EGFR) but is without effect on the growth of anothercarcinoma that does not express the EGF receptor. Thus, selectiveinhibitors of certain receptor tyrosine kinases, are useful in thetreatment of abnormal cell growth, in particular cancer, in mammals. Inaddition to receptor tyrosine kinses, selective inhibitors of certainnon-receptor tyrosine kinases, such as FAK (focal adhesion kinase), lck,src, abl or serine/threonine kinases (e.g.: cyclin dependent kinases,are useful in the treatment of abnormal cell growth, in particularcancer, in mammals. FAK is also known as the Protein-Tyrosine Kinase 2,PTK2.

Convincing evidence suggests that FAK, a cytoplasmic, non-receptortyrosine kinase, plays an essential role in cell-matrix signaltransduction pathways (Clark and Brugge 1995, Science 268: 233-239) andits aberrant activation is associated with an increase in the metastaticpotential of tumors (Owens et al. 1995, Cancer Research 55: 2752-2755).FAK was originally identified as a 125 kDa protein highlytyrosine-phosphorylated in cells transformed by v-Src. FAK wassubsequently found to be a tyrosine kinase that localizes to focaladhesions, which are contact points between cultured cells and theirunderlying substratum and sites of intense tyrosine phosphorylation. FAKis phosphorylated and, thus, activated in response to extracellularmatrix (ECM)-binding to integrins. Recently, studies have demonstratedthat an increase in FAK mRNA levels accompanied invasive transformationof tumors and attenuation of the expression of FAK (through the use ofantisense oligonucleotides) induces apoptosis in tumor cells (Xu et al.1996, Cell Growth and Diff. 7: 413-418). In addition to being expressedin most tissue types, FAK is found at elevated levels in most humancancers, particularly in highly invasive metastases.

Various compounds, such as styrene derivatives, have also been shown topossess tyrosine kinase inhibitory properties. Five European patentpublications, namely EP 0 566 226 A1 (published Oct. 20, 1993), EP 0 602851 A1 (published Jun. 22, 1994), EP 0 635 507 A1 (published Jan. 25,1995), EP 0 635 498 A1 (published Jan. 25, 1995), and EP 0 520 722 A1(published Dec. 30, 1992), refer to certain bicyclic derivatives, inparticular quinazoline derivatives, as possessing anti-cancer propertiesthat result from their tyrosine kinase inhibitory properties.

Also, World patent application WO 92/20642 (published Nov. 26, 1992),refers to certain bis-mono and bicyclic aryl and heteroaryl compounds astyrosine kinase inhibitors that are useful in inhibiting abnormal cellproliferation. World patent applications WO96/16960 (published Jun. 6,1996), WO 96/09294 (published Mar. 6, 1996), WO 97/30034 (published Aug.21, 1997), WO 98/02434 (published Jan. 22, 1998), WO 98/02437 (publishedJan. 22, 1998), and WO 98/02438 (published Jan. 22, 1998), also refer tosubstituted bicyclic heteroaromatic derivatives as tyrosine kinaseinhibitors that are useful for the same purpose.

U.S. Patent Application Ser. No. 60/435,670, filed Dec. 20, 2002(Attorney Docket No. PC25339) relates to a broad class of novelpyrimidine derivatives that are selective inhibitors of FAK. As such,these compounds are useful in the treatment of abnormal cell growth.

Accordingly, a need exists for additional selective inhibitors ofcertain receptor and non-receptor tyrosine kinases, useful in thetreatment of abnormal cell growth, such as cancer, in mammals. Thepresent invention provides for novel pyrimidine derivatives that areselective inhibitors of the non-receptor tyrosine kinase, FAK, and areuseful in the treatment of abnormal cell growth.

SUMMARY OF THE INVENTION

The present invention relates to a compound of the formula 1

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof,

wherein n is an integer from 1 to 3;

each R¹ is a substituent independently selected from the groupconsisting of hydrogen, hydroxy, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₈)heterocyclyl, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,—O(C₂-C₈)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —CO₂R⁵, —CONR⁵R⁶,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷; with the proviso that aheteroatom of the foregoing R¹ substituents may not be bound to an sp³carbon atom bound to another heteroatom; and said R¹ substituents,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₂-C₈)heterocyclyl, —O(C₁-C₆)alkyl,—O(C₃-C₇)cycloalkyl, O(C₂-C₈)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷,—CO₂R⁵, —CONR⁵R⁶, SO₂NR⁵R⁶, —NHCOR⁵—NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ groups areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, —CF₃, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; with the proviso that a heteroatom of theforegoing optional R¹ moieties may not be bound to an sp³ carbon atombound to another heteroatom;

each R² is a substituent independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, and —CONR⁵R⁶; with theproviso that a heteroatom of any of the foregoing R² substituents maynot be bound to an sp³ carbon atom that is bound to another heteroatom;and said R² substituents, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, and—CONR⁵R⁶, are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CF₃, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and with the provisothat a heteroatom of the foregoing optional R² moieties may not be boundto an sp³ carbon atom bound to another heteroatom;

R¹ and R² may be taken together with the atom(s) to which they areattached to form a cyclic group, —(C₃-C₁₀)cycloalkyl or—(C₂-C₉)heterocyclyl, wherein said cyclic group is optionallysubstituted by one to three moieties selected from the group consistingof hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties ofsaid cyclic group may be optionally substituted by one to three R⁵groups, and said cyclic group is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR⁵, with the proviso that any of the foregoing cyclicgroup moieties or elements may not be bound to an sp³ carbon atom thatis bound to another heteroatom;

R³ is a suitable substituent, including, but not limited to asubstituent selected from the group consisting of:

-   -   (a) hydrogen;    -   (b) —(C₆-C₁₀)aryl or —(C₁-C₉)heteroaryl, optionally substituted        by one to three moieties independently selected from the group        consisting of halogen, hydroxy, —(C₁-C₆)alkyl,        —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl,        (C₆-C₁₀)aryl, (C₂-C₉)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶,        —NHSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl        —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),        —N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,        —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,        —(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl,        —(CO)(C₂-C₈)heterocyclyl, —(CO)(C₁-C₉)heteroaryl,        —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,        —(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl,        —(CO)O(C₁-C₉)heteroaryl, —(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl,        —SO₂N((C₁-C₆)alkyl)₂, —SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and        —SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₆-C₁₀) aryl or        —(C₁-C₉) heteroaryl are optionally interrupted by one to three        elements selected from the group consisting of —(C═O), —SO₂,        —S—, —O—, —N—, —NH— and —NR⁵; and R⁵ and R⁶ of said NR⁵R⁶R³(b)        group may be taken together with the atoms to which they are        attached to form a —(C₂-C₉)heterocyclyl;    -   (c) —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocyclyl, and        —(C₁-C₆)alkyl—(C₂-C₉) heterocyclyl, optionally substituted by        one to three moieties independently selected from the group        consisting of halogen, hydroxy, —(C₁-C₆)alkyl,        —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl,        (C₆-C₁₀)aryl, (C₂-C₈)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶,        —NSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl,        —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),        —N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,        —O—SO₂(C₁-C₆)alkyl, —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl,        —(CO)CF₃, —(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl,        —(CO)(C₂-C₈)heterocyclyl, —(CO)(C₁-C₉)heteroaryl,        —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,        —(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₈)heterocyclyl,        —(CO)O(C₁-C₉)heteroaryl, —(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl,        —SO₂N((C₁-C₆)alkyl)₂, —SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and        —SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said        —(C₃-C₁₀)cycloalkyl, —(C₂-C₈)heterocyclyl, and        —(C₁-C₆)alkyl—(C₂-C₉) heterocyclyl are optionally interrupted by        one to three elements selected from the group consisting of        —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR⁵; and R⁵ and R⁶ of        said NR⁵R⁶R³(b) group may be taken together with the atoms to        which they are attached to form a —(C₂-C₉)heterocyclyl;    -   (d) —(C₁-C₆)alkyl optionally substituted by one to three        moieties selected from the group consisting of halogen, hydroxy,        —(C₁-C₆)alkyl, —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂,        —(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₂-C₉)heterocyclyl,        —(C₁-C₉)heteroaryl, —NR⁵R⁶, —NSO₂(C₁-C₆)alkyl,        —NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),        —N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,        —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,        —(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl,        —(CO)(C₂-C₉)heterocyclyl, —(CO)(C₁-C₉)heteroaryl,        —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,        —(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl,        —(CO)O(C₁-C₉)heteroaryl, —(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl,        —SO₂N((C₁-C₆)alkyl)₂, —SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and        —SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₁-C₆)alkyl is        optionally interrupted by one to three elements selected from        the group consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and        —NR⁵; and R⁵ and R⁶ of said NR⁵R⁶R³(b) group may be taken        together with the atoms to which they are attached to form a        —(C₂-C₉)heterocyclyl;

and wherein each R³ (b)-(d) substituent, moiety, or element isoptionally substituted by one to three radicals independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂,—CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₇)cycloalkyl, —(C₂-C₈)heterocyclyl, —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,—O(C₂-C₉)heterocyclyl, —C═N—OH, —C═N—O(C₁-C₆ alkyl), —NR⁵R⁶, —SR⁷,—SOR⁷, —SO₂R⁷, —CO₂R⁵, —CONR⁵R⁶, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷; with the proviso that a heteroatom of the foregoing R³(b)-(d) substituents, moieties, elements or radicals may not be bound toan sp³ carbon atom bound to another heteroatom; and wherein R⁵ and R⁶ ofsaid —NR⁵R⁶, —CONR⁵R⁶, —SO₂NR⁵R⁶, and —NR⁵CONR⁵R⁶ groups may be takentogether with the atoms to which they are attached to form a—(C₂-C₉)heterocyclyl;

R⁴ is a substituent selected from the group consisting of hydrogen,(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, and —(C₂-C₉)heterocyclyl; wherein said(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, and —(C₂-C₉)heterocyclyl R⁴substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,—(C₁-C₆)alkyl, —CN, —NR⁵ ₂, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, and —CONR⁵R⁸; with the proviso that aheteroatom of the foregoing R⁴ substituents may not be bound to an sp³carbon atom bound to another heteroatom; and wherein R⁵ and R⁸ of said—CONR⁵R⁸ group may be taken together with the atoms to which they areattached to form a —(C₃-C₁₀)cycloalkyl or —(C₂-C₈)heterocyclyl;

R⁵ and R⁶ are each substituents independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; whereinsaid —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl R⁵ or R⁶ substituents areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, —CF₃, —CN,—(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —NH(C₃-C₇)cycloalkyl,—NH(C₂-C₉)heterocyclyl, —NH(C₆-C₁₀)aryl, —NH(C₁-C₉)heteroaryl,—N((C₁-C₆)alkyl)₂, —N((C₃-C₇)cycloalkyl)₂, —N((C₂-C₉)heterocyclyl)₂,—N((C₆-C₁₀)aryl)₂, —N((C₁-C₉)heteroaryl)₂, —O(C₁-C₆)alkyl,—O(C₃-C₇)cycloalkyl, —O(C₂-C₉)heterocyclyl, —O(C₆-C₁₀)aryl,—O(C₂-C₉)heteroaryl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁷,—CONR², —CONR⁷, and —CONR⁷R⁸; with the proviso that a heteroatom of theforegoing R⁵ or R⁶ substituents or moieties may not be bound to an sp³carbon atom bound to another heteroatoms; and wherein R⁷ and R⁸ of said—CONR⁷R⁸ group may be taken together with the atoms to which they areattached to form a —(C₁-C₉) heteroaryl;

R⁵ and R⁶ may be taken together with the atom(s) to which they areattached to form a cyclic group, —(C₃-C₁₀)cycloalkyl or—(C₂-C₈)heterocyclyl, wherein said cyclic group is optionallysubstituted by one to three moieties selected from the group consistingof hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁹, —CONR⁵R⁶,—CONR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties ofsaid cyclic group may be optionally substituted by one to three R⁷groups, and said cyclic group is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR⁵, with the proviso that any of the foregoing cyclicgroup moieties or elements may not be bound to an sp³ carbon atom thatis bound to another heteroatom;

R⁷ is a substituent selected from the group consisting of —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉) heteroaryl R⁷substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵ ₂, and —O(C₁-C₆)alkyl, with theproviso that a heteroatom of the foregoing R⁷ substituents or moietiesmay not be bound to an sp³ carbon atom bound to another heteroatom;

R⁸ is a substituent selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl,and —(C₁-C₉) heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉) heteroaryl R⁸ radicalsare optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NH₂, —NHR⁹, —NR⁹ ₂, OR⁹, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R¹⁰, —CONH₂, —CONHR¹⁰, and —CONR¹⁰R¹¹; withthe proviso that a heteroatom of the foregoing R⁸ substituents ormoieties may not be bound to an sp³ carbon atom bound to anotherheteroatom; and wherein R¹⁰ and R¹¹ of —CONR¹⁰R¹¹ may be taken togetherwith the atoms to which they are attached to form a—(C2-C₉)heterocyclyl;

R⁹ and R¹⁰ are each —(C₁-C₆)alkyl and may be taken together with theatoms to which they are attached to form a —(C₂-C₉)heterocyclyl; and

R¹¹ is hydrogen or —(C₁-C₆)alkyl.

In a preferred embodiment, the present invention relates to a compoundof the formula I

or a pharmaceutically acceptable salt, solvate, hydrate, or prodrugthereof,

wherein n is an integer from 1 to 3;

each R¹ is a substituent independently selected from the groupconsisting of hydrogen, hydroxy, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,—O(C₂-C₉)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —CO₂R⁵, —CONR⁵R⁶,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷; with the proviso that aheteroatom of the foregoing R¹ substituents may not be bound to an sp³carbon atom bound to another heteroatom; and said R¹ substituents,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —O(C₁-C₆)alkyl,—O(C₃-C₇)cycloalkyl, O(C₂-C₉)heterocyclyl, —NR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷,—CO₂R⁵, —CONR⁵R⁶, SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ groupsare optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CF₃,—CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; with the provisothat a heteroatom of the foregoing optional R¹ moieties may not be boundto an sp³ carbon atom bound to another heteroatom;

each R² is a substituent independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, and —CONR⁵R⁶; with theproviso that a heteroatom of any of the foregoing R² substituents maynot be bound to an sp³ carbon atom that is bound to another heteroatom;and said R² substituents, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, and—CONR⁵R⁶, are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CF₃, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁶,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and with the provisothat a heteroatom of the foregoing optional R² moieties may not be boundto an sp³ carbon atom bound to another heteroatom;

R¹ and R² may be taken together with the atom(s) to which they areattached to form a cyclic group, —(C₃-C₁₀)cycloalkyl or—(C₂-C₉)heterocyclyl, wherein said cyclic group is optionallysubstituted by one to three moieties selected from the group consistingof hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties ofsaid cyclic group may be optionally substituted by one to three R⁵groups, and said cyclic group is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR⁵, with the proviso that any of the foregoing cyclicgroup moieties or elements may not be bound to an sp³ carbon atom thatis bound to another heteroatom;

R³ is a substituent selected from the group consisting of:

-   -   (a) hydrogen;    -   (c) —(C₆-C₁₀)aryl or —(C₁-C₉)heteroaryl, optionally substituted        by one to three moieties independently selected from the group        consisting of halogen, hydroxy, —(C₁-C₆)alkyl,        —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl,        (C₆-C₁₀)aryl, (C₂-C₈)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶,        —NHSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl        —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),        —N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,        —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,        —(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl,        —(CO)(C₂-C₉)heterocyclyl, —(CO)(C₁-C₉)heteroaryl,        —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,        —(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl,        —(CO)O(C₁-C₉)heteroaryl, —(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl,        —SO₂N((C₁-C₆)alkyl)₂, —SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and        —SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₆-C₁₀) aryl or        —(C₁-C₉) heteroaryl are optionally interrupted by one to three        elements selected from the group consisting of —(C═O), —SO₂,        —S—, —O—, —N—, —NH— and —NR⁵; and R⁵ and R⁶ of said NR⁵R⁶R³(b)        group may be taken together with the atoms to which they are        attached to form a —(C₂-C₉)heterocyclyl;    -   (c) —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocyclyl, and        —(C₁-C₆)alkyl—(C₂-C₉) heterocyclyl, optionally substituted by        one to three moieties independently selected from the group        consisting of halogen, hydroxy, —(C₁-C₆)alkyl,        —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl,        (C₆-C₁₀)aryl, (C₂-C₉)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶,        —NSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl,        —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),        —N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,        —O—SO₂(C₁-C₆)alkyl, —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl,        —(CO)CF₃, —(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl,        —(CO)(C₂-C₉)heterocyclyl, —(CO)(C₁-C₉)heteroaryl,        —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,        —(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl,        —(CO)O(C₁-C₉)heteroaryl, —(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl,        —SO₂N((C₁-C₆)alkyl)₂, —SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and        —SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said        —(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocyclyl, and        —(C₁-C₆)alkyl—(C₂-C₉) heterocyclyl are optionally interrupted by        one to three elements selected from the group consisting of        —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR⁵; and R⁵ and R⁶ of        said NR⁵R⁶R³(b) group may be taken together with the atoms to        which they are attached to form a —(C₂-C₉)heterocyclyl;    -   (d) —(C₁-C₆)alkyl optionally substituted by one to three        moieties selected from the group consisting of halogen, hydroxy,        —(C₁-C₆)alkyl, —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂,        —(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl, (C₂-C₉)heterocyclyl,        —(C₁-C₉)heteroaryl, —NR⁵R⁶, —NSO₂(C₁-C₆)alkyl,        —NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),        —N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,        —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,        —(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl,        —(CO)(C₂-C₉)heterocyclyl, —(CO)(C₁-C₉)heteroaryl,        —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,        —(CO)O(C₆-C₁₀)aryl, (CO)O(C₂-C₉)heterocyclyl,        —(CO)O(C₁-C₉)heteroaryl, —(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl,        —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂,        SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl,        —SO₂N((C₁-C₆)alkyl)₂, —SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and        —SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₁-C₆)alkyl is        optionally interrupted by one to three elements selected from        the group consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and        —NR⁵; and R⁵ and R⁶ of said NR⁵R⁶R³(b) group may be taken        together with the atoms to which they are attached to form a        —(C₂-C₈)heterocyclyl;

and wherein each R³ (b)-(d) substituent, moiety, or element isoptionally substituted by one to three radicals independently selectedfrom the group consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂,—CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl,—(C₁-C₉)heteroaryl, —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl,—O(C₂-C₉)heterocyclyl, —C═N—OH, —C═N—O(C₁-C₆ alkyl), —NR⁵R⁶, —SR⁷,—SOR⁷, —SO₂R⁷, —CO₂R⁵, —CONR⁵R⁶, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷; with the proviso that a heteroatom of the foregoing R³(b)-(d) substituents, moieties, elements or radicals may not be bound toan sp³ carbon atom bound to another heteroatom; and wherein R⁵ and R⁶ ofsaid —NR⁵R⁶, —CONR⁵R⁶, —SO₂NR⁵R⁶, and —NR⁵CONR⁵R⁶ groups may be takentogether with the atoms to which they are attached to form a—(C₂-C₉)heterocyclyl;

R⁴ is a substituent selected from the group consisting of hydrogen,(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, and —(C2-C₉)heterocyclyl; wherein said(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, and —(C₂-C₉)heterocyclyl R⁴substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,—(C₁-C₆)alkyl, —CN, —NR⁵ ₂, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, and —CONR⁵R⁸; with the proviso that aheteroatom of the foregoing R⁴ substituents may not be bound to an sp³carbon atom bound to another heteroatom; and wherein R⁵ and R⁸ of said—CONR⁵R⁸ group may be taken together with the atoms to which they areattached to form a —(C₃-C₁₀)cycloalkyl or —(C₂-C₉)heterocyclyl;

R⁵ and R⁶ are each substituents independently selected from the groupconsisting of hydrogen, —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; whereinsaid —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl R⁵ or R⁶ substituents areoptionally substituted by one to three moieties independently selectedfrom the group consisting of hydrogen, halogen, —CF₃, —CN,—(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —NH(C₃-C₇)cycloalkyl,—NH(C₂-C₉)heterocyclyl, —NH(C₆-C₁₀)aryl, —NH(C₁-C₉)heteroaryl,—N((C₁-C₆)alkyl)₂, —N((C₃-C₇)cycloalkyl)₂, —N((C₂-C₉)heterocyclyl)₂,—N((C₆-C₁₀)aryl)₂, —N((C₁-C₉)heteroaryl)₂, —O(C₁-C₆)alkyl,—O(C₃-C₇)cycloalkyl, —O(C₂-C₉)heterocyclyl, —O(C₆-C₁₀)aryl,—O(C₁-C₉)heteroaryl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁷,—CONH₂, —CONHR⁷, and —CONR⁷R⁸; with the proviso that a heteroatom of theforegoing R⁵ or R⁶ substituents or moieties may not be bound to an sp³carbon atom bound to another heteroatoms; and wherein R⁷ and R⁸ of said—CONR⁷R⁸ group may be taken together with the atoms to which they areattached to form a —(C₁-C₉) heteroaryl;

R⁵ and R⁶ may be taken together with the atom(s) to which they areattached to form a cyclic group, —(C₃-C₁₀)cycloalkyl or—(C₂-C₉)heterocyclyl, wherein said cyclic group is optionallysubstituted by one to three moieties selected from the group consistingof hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR₅R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties ofsaid cyclic group may be optionally substituted by one to three R⁷groups, and said cyclic group is optionally interrupted by one to threeelements selected from the group consisting of —(C═O), —SO₂, —S—, —O—,—N—, —NH— and —NR⁵, with the proviso that any of the foregoing cyclicgroup moieties or elements may not be bound to an sp³ carbon atom thatis bound to another heteroatom;

R⁷ is a substituent selected from the group consisting of —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₈)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉) heteroaryl R⁷substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵ ₂, and —O(C₁-C₆)alkyl, with theproviso that a heteroatom of the foregoing R⁷ substituents or moietiesmay not be bound to an sp³ carbon atom bound to another heteroatom;

R⁸ is a substituent selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl,and —(C₁-C₉) heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉) heteroaryl R⁸ radicalsare optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NH₂, —NHR⁹, —NR⁹ ₂, OR⁹, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R¹⁰, —CONH₂, —CONHR¹⁰, and —CONR¹⁰R¹¹; withthe proviso that a heteroatom of the foregoing R⁸ substituents ormoieties may not be bound to an sp³ carbon atom bound to anotherheteroatom; and wherein R¹⁰ and R¹¹ of —CONR¹⁰R¹¹ may be taken togetherwith the atoms to which they are attached to form a—(C2-C₉)heterocyclyl;

R⁹ and R¹⁰ are each —(C₁-C₆)alkyl and may be taken together with theatoms to which they are attached to form a —(C₂-C₉)heterocyclyl; and

R¹¹ is hydrogen or —(C₁-C₆)alkyl.

The present invention also includes isotopically-labeled compounds,which are identical to those recited in Formula 1, but for the fact thatone or more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically-labelled compounds of Formula 1 of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the Schemes and/or in the Examples andPreparations below, by substituting a readily availableisotopically-labelled reagent for a non-isotopically-labelled reagent.

The present invention also relates to the pharmaceutically acceptableacid addition salts of compounds of the formula 1. The acids which areused to prepare the pharmaceutically acceptable acid addition salts ofthe aforementioned base compounds of this invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the chloride, bromide, iodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate,citrate, acid citrate, tartrate, bitartrate, succinate, maleate,fumarate, gluconate, saccharate, benzoate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.

The invention also relates to base addition salts of formula 1. Thechemical bases that may be used as reagents to prepare pharmaceuticallyacceptable base salts of those compounds of formula 1 that are acidic innature are those that form non-toxic base salts with such compounds.Such non-toxic base salts include, but are not limited to those derivedfrom such pharmacologically acceptable cations such as alkali metalcations (e.g., potassium and sodium) and alkaline earth metal cations(e.g., calcium and magnesium), ammonium or water-soluble amine additionsalts such as N-methylglucamine-(meglumine), and the loweralkanolammonium and other base salts of pharmaceutically acceptableorganic amines.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, includes salts of acidic or basic groups which maybe present in the compounds of the present invention. The compounds ofthe present invention that are basic in nature are capable of forming awide variety of salts with various inorganic and organic acids. Theacids that may be used to prepare pharmaceutically acceptable acidaddition salts of such basic compounds of are those that form non-toxicacid addition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate,lactate, salicylate, citrate, acid citrate, tartrate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucuronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonateand pamoate [i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)]salts.The compounds of the present invention that include a basic moiety, suchas an amino group, may form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above.

This invention also encompasses pharmaceutical compositions containingprodrugs of compounds of the formula 1. Compounds of formula 1 havingfree amino, amido, hydroxy or carboxylic groups can be converted intoprodrugs. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues which are covalently joined through peptide bonds to freeamino, hydroxy or carboxylic acid groups of compounds of formula 1. Theamino acid residues include the 20 naturally occurring amino acidscommonly designated by three letter symbols and also include,4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline, homocysteine, homoserine, ornithine and methionine sulfone.Prodrugs also include compounds wherein carbonates, carbamates, amidesand alkyl esters that are covalently bonded to the above substituents offormula 1 through the carbonyl carbon prodrug sidechain.

This invention also encompasses compounds of formula 1 containingprotective groups. One skilled in the art will also appreciate thatcompounds of the invention can also be prepared with certain protectinggroups that are useful for purification or storage and can be removedbefore administration to a patient. The protection and deprotection offunctional groups is described in “Protective Groups in OrganicChemistry”, edited by J. W. F. McOmie, Plenum Press (1973) and“Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene andP. G. M. Wuts, Wiley-Interscience (1999).

The compounds of this invention include all stereoisomers (e.g., cis andtrans isomers) and all optical isomers of compounds of the formula 1(e.g., R and S enantiomers), as well as racemic, diastereomeric andother mixtures of such isomers.

The compounds, salts and prodrugs of the present invention can exist inseveral tautomeric forms, including the enol and imine form, and theketo and enamine form and geometric isomers and mixtures thereof. Allsuch tautomeric forms are included within the scope of the presentinvention. Tautomers exist as mixtures of a tautomeric set in solution.In solid form, usually one tautomer predominates. Even though onetautomer may be described, the present invention includes all tautomersof the present compounds.

The present invention also includes atropisomers of the presentinvention. Atropisomers refer to compounds of formula 1 that can beseparated into rotationally restricted isomers.

The compounds of this invention may contain olefin-like double bonds.When such bonds are present, the compounds of the invention exist as cisand trans configurations and as mixtures thereof.

A “suitable substituent” is intended to mean a chemically andpharmaceutically acceptable functional group i.e., a moiety that doesnot negate the biological activity of the inventive compounds. Suchsuitable substituents may be routinely selected by those skilled in theart. Illustrative examples of suitable substituents include, but are notlimited to halo groups, perfluoroalkyl groups, perfluoroalkoxy groups,alkyl groups, alkenyl groups, alkynyl groups, hydroxy groups, oxogroups, mercapto groups, alkylthio groups, alkoxy groups, aryl orheteroaryl groups, aryloxy or heteroaryloxy groups, aralkyl orheteroaralkyl groups, aralkoxy or heteroaralkoxy groups, HO—(C═O)—groups, amino groups, alkyl- and dialkylamino groups, carbamoyl groups,alkylcarbonyl groups, alkoxycarbonyl groups, alkylaminocarbonyl groupsdialkylamino carbonyl groups, arylcarbonyl groups, aryloxycarbonylgroups, alkylsulfonyl groups, arylsulfonyl groups and the like. Thoseskilled in the art will appreciate that many substituents can besubstituted by additional substituents. Further examples of suitablesubstituents include those recited in the definition of compounds ofFormula 1, including R¹ through R¹¹, as defined hereinabove.

The term “interrupted by” refers to compounds in which a ring carbonatom is replaced by an element selected from the group consisting of—(C═O), —SO², —S—, —O—, —N—, —NH—, and —NR⁵. For example, if R⁷ is—(C₆-C₁₀)aryl, such as

the ring may be interrupted or replaced by a nitrogen heteroatom to formthe following ring:

such that a ring carbon is replaced by the heteroatom nitrogen.Compounds of the invention can accommodate up to three such replacementsor interruptions.

As used herein, the term “alkyl,” as well as the alkyl moieties of othergroups referred to herein (e.g., alkoxy), may be linear or branched(such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl,secondary-butyl, tertiary-butyl); optionally substituted by 1 to 3suitable substituents as defined above such as fluoro, chloro,trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy, trifluoromethoxy,difluoromethoxy or (C₁-C₆)alkyl. The phrase “each of said alkyl” as usedherein refers to any of the preceding alkyl moieties within a group suchalkoxy, alkenyl or alkylamino. Preferred alkyls include (C₁-C₆)alkyl,more preferred are (C₁-C₄)alkyl, and most preferred are methyl andethyl.

As used herein, the term “cycloalkyl” refers to a mono, bicyclic ortricyclic carbocyclic ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclopentenyl,cyclohexenyl, bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl andbicyclo[5.2.0]nonanyl, etc.); optionally containing 1 or 2 double bondsand optionally substituted by 1 to 3 suitable substituents as definedabove such as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “halogen” includes fluoro, chloro, bromo oriodo or fluoride, chloride, bromide or iodide.

As used herein, the term “alkenyl” means straight or branched chainunsaturated radicals of 2 to 6 carbon atoms, including, but not limitedto ethenyl, 1-propenyl, 2-propenyl(allyl), iso-propenyl,2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “alkynyl” is used herein to mean straight orbranched hydrocarbon chain radicals having one triple bond including,but not limited to, ethynyl, propynyl, butynyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

As used herein, the term “carbonyl” or “(C═O)” (as used in phrases suchas alkylcarbonyl, alkyl—(C═O)— or alkoxycarbonyl) refers to the joinderof the >C═O moiety to a second moiety such as an alkyl or amino group(i.e. an amido group). Alkoxycarbonylamino (i.e. alkoxy(C═O)—NH—) refersto an alkyl carbamate group. The carbonyl group is also equivalentlydefined herein as (C═O). Alkylcarbonylamino refers to groups such asacetamide.

As used herein, the term “aryl” means aromatic radicals such as phenyl,naphthyl, tetrahydronaphthyl, indanyl and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above.

As used herein, the term “heteroaryl” refers to an aromatic heterocyclicgroup usually with one heteroatom selected from O, S and N in the ring.In addition to said heteroatom, the aromatic group may optionally haveup to four N atoms in the ring. For example, heteroaryl group includespyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thienyl, furyl,imidazolyl, pyrrolyl, oxazolyl (e.g., 1,3-oxazolyl, 1,2-oxazolyl),thiazolyl (e.g., 1,2-thiazolyl, 1,3-thiazolyl), pyrazolyl, tetrazolyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), oxadiazolyl (e.g.,1,2,3-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), quinolyl,isoquinolyl, benzothienyl, benzofuryl, indolyl, and the like; optionallysubstituted by 1 to 3 suitable substituents as defined above such asfluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy, (C₆-C₁₀)aryloxy,trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

The term “heterocyclic” as used herein refers to a cyclic groupcontaining 1-9 carbon atoms and 1 to 4 hetero atoms selected from N, O,S(O)_(n) or NR. Examples of such rings include azetidinyl,tetrahydrofuranyl, imidazolidinyl, pyrrolidinyl, piperidinyl,piperazinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,thiomorpholinyl, tetrahydrothiazinyl, tetrahydro-thiadiazinyl,morpholinyl, oxetanyl, tetrahydrodiazinyl, oxazinyl, oxathiazinyl,indolinyl, isoindolinyl, quinuclidinyl, chromanyl, isochromanyl,benzoxazinyl, and the like. Examples of said monocyclic saturated orpartially saturated ring systems are tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, imidazolidin-1-yl, imidazolidin-2-yl,imidazolidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperazin-1-yl,piperazin-2-yl, piperazin-3-yl, 1,3-oxazolidin-3-yl, isothiazolidine,1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl,thiomorpholin-yl, 1,2-tetrahydrothiazin-2-yl,1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazin-yl, morpholin-yl,1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, 1,4-oxazin-2-yl,1,2,5-oxathiazin-4-yl and the like; optionally containing 1 or 2 doublebonds and optionally substituted by 1 to 3 suitable substituents asdefined above such as fluoro, chloro, trifluoromethyl, (C₁-C₆)alkoxy,(C₆-C₁₀)aryloxy, trifluoromethoxy, difluoromethoxy or (C₁-C₆)alkyl.

Nitrogen heteroatoms as used herein refers to N═, >N and —NH; wherein—N═ refers to a nitrogen double bond; >N refers to a nitrogen containingtwo bond connections and —N refers to a nitrogen containing one bond.

“Embodiment” as used herein refers to specific groupings of compounds oruses into discrete subgenera. Such subgenera may be cognizable accordingto one particular substituent such as a specific R¹ or R¹³ group. Othersubgenera are cognizable according to combinations of varioussubstituents, such as all compounds wherein R² is hydrogen and R¹ is(C₁-C₆)alkyl.

Thus, the present invention provides a compound of formula 1, wherein R¹is selected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶ and —CONR⁵R⁸.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³. In a preferredembodiment, R¹ is —O(C₁-C₆)alkyl, optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR₅R⁶ optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶ optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸. In a preferred embodiment, R¹ is —SO₂NR⁵R⁶, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R³. In a preferred embodiment, R¹ is —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶and —CONR⁵R⁸.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁵,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups.

Also provided is a compound of formula 1 wherein R¹ is selected fromhydrogen, hydroxy, and —(C₁-C₆)alkyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸;and R² is hydrogen or —(C₁-C₆)alkyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, (C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; and R² is hydrogen.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶ and —CONR⁵R⁸; and R² is hydrogen.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; and R² is hydrogen.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; and R² is hydrogen.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶ optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CON⁵R⁶ and —CONR⁵; and R² is hydrogen.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; and R² is hydrogen.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R³; and R² is hydrogen.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; and R¹ is hydrogen.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; and R¹ ishydrogen.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁶,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and R¹ is hydrogen.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R³; and R² is —(C₁-C₆)alkyl.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; and R² is—(C₁-C₆)alkyl.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; and R² is—(C₁-C₆)alkyl.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; and R² is—(C₁-C₆)alkyl.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶ optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; and R² is —(C₁-C₆)alkyl.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and—CONR⁵R⁸; and R² is —(C₁-C₆)alkyl.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R³; and R² is —(C₁-C₆)alkyl.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; and R¹ is —(C₁-C₆)alkyl.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; and R¹ is—(C₁-C₆)alkyl.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and R¹ is—(C₁-C₆)alkyl.

Also provided is a compound of formula 1 wherein R¹ is selected fromhydrogen, hydroxy, and —(C₁-C₆)alkyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸;R² is hydrogen or —(C₁-C₆)alkyl, optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and n is 1.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R³; R² is —(C₁-C₆)alkyl; and n is 1.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is—(C₁-C₆)alkyl; and n is 1.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is—(C₁-C₆)alkyl; and n is 1.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is—(C₁-C₆)alkyl; and n is 1.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶, optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is —C₁-C₆)alkyl; and n is 1.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶ optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₈)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 1.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷,—SO₂R⁷—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl; and n is 1.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; R¹ is—(C₁-C₆)alkyl; and n is 1.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR₅R⁸,—SK⁷, —SOK⁷, —SO₂K⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂K⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl;and n is 1.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 1.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is—(C₁-C₆)alkyl; and n is 1.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C2-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is—(C₁-C₆)alkyl; and n is 1.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is—(C₁-C₆)alkyl; and n is 1.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶, optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 1.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵—(C₃-C₇)cycloalkyl, —(C₂-C₈)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 1.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁵, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl; and n is 1.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁶, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; R¹ is—(C₁-C₆)alkyl; and n is 1.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl;and n is 1.

Also provided is a compound of formula 1 wherein R¹ is selected fromhydrogen, hydroxy, and —(C₁-C₆)alkyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³;R² is hydrogen or —(C₁-C₆)alkyl, optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR5, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and n is 1.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is hydrogen; and n is 1.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶ and —CONR⁵R⁸; R² is hydrogen; andn is 1.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is hydrogen; andn is 1.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is hydrogen; andn is 1.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶, optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is hydrogen; and n is 1.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₈)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R¹ is hydrogen; and n is 1.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R³; R² is hydrogen; and n is 1.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R¹ is hydrogen; and n is 1.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; R¹ is hydrogen;and n is 1.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; R¹ is hydrogen; and nis 1.

Also provided is a compound of formula 1 wherein R¹ is selected fromhydrogen, hydroxy, and —(C₁-C₆)alkyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸;R² is hydrogen or —(C₁-C₆)alkyl, optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and n is 2.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 2.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶ and —CONR⁵R³; R² is —(C₁-C₆)alkyl;and n is 2.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is—(C₁-C₆)alkyl; and n is 2.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is—(C₁-C₆)alkyl; and n is 2.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶, optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is —(C₁-C₆)alkyl; and n is 2.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶ optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₈)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 2.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 2.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl; and n is 2.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR5 NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; R¹ is—(C₁-C₆)alkyl; and n is 2.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl;and n is 2.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 2.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is—(C₁-C₆)alkyl; and n is 2.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is—(C₁-C₆)alkyl; and n is 2.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is—(C₁-C₆)alkyl; and n is 2.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶, optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R³; R² is —(C₁-C₆)alkyl; and n is 2.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶ optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 2.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is —(C₁-C₆)alkyl; and n is 2.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷,—SO₂R⁷—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl; and n is 2.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; R¹ is—(C₁-C₆)alkyl; and n is 2.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁵,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; R¹ is —(C₁-C₆)alkyl;and n is 2.

Also provided is a compound of formula 1 wherein R¹ is selected fromhydrogen, hydroxy, and —(C₁-C₆)alkyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸;R² is hydrogen or —(C₁-C₆)alkyl, optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁵,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; and n is 2.

The invention further provides a compound of formula 1 wherein R¹ isselected from hydrogen, hydroxy, and —(C₁-C₆)alkyl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is hydrogen; and n is 2.

The present invention further provides a compound of formula 1, whereinR¹ is —(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶ and —CONR⁵R⁵; R² is hydrogen; andn is 2.

The present invention also provides a compound of formula 1 wherein R¹is selected from the group consisting of —(C₃-C₇)cycloalkyl and—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is hydrogen; andn is 2.

The invention also contemplates compounds of formula 1 wherein R¹ isselected from —O(C₁-C₆)alkyl, —O(C₃-C₇)cycloalkyl, and—O(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is hydrogen; andn is 2.

One embodiment of the invention is a compound of formula 1 wherein R¹ is—NR⁵R⁶ optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl,—CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is hydrogen; and n is 2.

A further embodiment of the invention is a compound of formula 1 whereinR¹ is selected from —SR⁷, —SOR⁷, —SO₂R⁷, and —SO₂NR⁵R⁶ optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵K⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is hydrogen; and n is 2.

The present invention also provides compounds of formula 1 wherein R¹ is—CO₂R⁵, —CONR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, or —NR⁵SO₂R⁷, optionallysubstituted by one to three moieties independently selected from thegroup consisting of hydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl,—NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶and —CONR⁵R⁸; R² is hydrogen; and n is 2.

Also provided is a compound of formula 1 wherein R² is hydrogen or—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷ wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R¹ is hydrogen; and n is 2.

Further provided is a compound of formula 1 wherein R² is—(C₃-C₇)cycloalkyl, or —(C₂-C₉)heterocyclyl, optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl,—(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶,—OR⁵, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶,—CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and—NR⁵SO₂R⁷, wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moietiesmay be optionally substituted by one to three R⁵ groups; R¹ is hydrogen;and n is 2.

Another embodiment of the present invention is a compound of formula 1wherein R² is —CO₂R⁵ and —CONR⁵R⁶ optionally substituted by one to threemoieties independently selected from the group consisting of hydrogen,halogen, hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl,—(C₂-C₆)alkynyl, —C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, CONR⁵R⁶, —CONR⁵R⁸,—SR⁷, —SOR⁷, —SO₂R⁷, —SO₂NR⁵R⁶, —NHCOR5, NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷,wherein said —(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may beoptionally substituted by one to three R⁵ groups; R¹ is hydrogen; and nis 2.

The present invention also provides a compound of formula 1 in which R¹and R² are taken together with the atom(s) to which they are attached toform a —(C₃-C₁₀)cycloalkyl optionally substituted by one to threemoieties selected from the group consisting of a hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O(C₁-C₆ alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R⁵ groups.

The present invention further provides a compound of formula 1 in whichR¹ and R² are taken together with the atom(s) to which they are attachedto form a —(C₂-C₉)heterocyclyl optionally substituted by one to threemoieties selected from the group consisting of a hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O(C₁-C₆ alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R⁵ groups.

The present invention also provides a compound of formula 1 in which R¹and R² are taken together with the atom(s) to which they are attached toform a —(C₃-C₁₀)cycloalkyl optionally substituted by one to threemoieties selected from the group consisting of a hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O(C₁-C₆ alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R⁵ groups; and n is 1.

The present invention further provides a compound of formula 1 in whichR¹ and R² are taken together with the atom(s) to which they are attachedto form a —(C₂-C₉)heterocyclyl optionally substituted by one to threemoieties selected from the group consisting of a hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O(C₁-C₆ alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R⁵ groups; and n is 1.

The present invention also provides a compound of formula 1 wherein R³is hydrogen.

Preferably, R³ is —(C₆-C₁₀)aryl or —(C₁-C₉)heteroaryl, optionallysubstituted by one to three moieties independently selected from thegroup consisting of halogen, hydroxy, —(C₁-C₆)alkyl,—(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,(C₂-C₉)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶, —NHSO₂(C₁-C₆)alkyl,—NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,—(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl, —(CO)(C₂-C₈)heterocyclyl,—(CO)(C₁-C₉)heteroaryl, —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,—(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl, —(CO)O(C₁-C₆)heteroaryl,—(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂, SO₂NH(C₁-C₆)alkyl,—SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and—SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₆-C₁₀)aryl or —(C₁-C₉)heteroaryl are optionally interrupted by one to three elements selectedfrom the group consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR⁵;and R⁵ and R⁶ of said NR⁵R⁶R³(b) group may be taken together with theatoms to which they are attached to form a —(C₂-C₉)heterocyclyl.

Alternatively, the invention provides a compound of formula 1 wherein R³is —(C₆-C₁₀)aryl, optionally substituted by one to three moietiesindependently selected from the group consisting of halogen, hydroxy,—(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl, —NHSO₂(C₁-C₆)alkyl,—NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, —SO₂NH₂,—SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶.

The invention also provides a compound of formula 1 wherein R³ is—(C₁-C₉)heteroaryl, optionally substituted by one to three moietiesindependently selected from the group consisting of halogen, hydroxy,—(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl, —NHSO₂(C₁-C₆)alkyl,—NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, —SO₂NH₂,—SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶.

Further, the invention provides a compound in which R³ is selected from—(C₃-C₁₀)cycloalkyl, —(C₂-C₉)heterocyclyl, and —(C₁-C₆)alkyl—(C₂-C₉)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of halogen, hydroxy,—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl,(C₆-C₁₀)aryl, (C₂-C₉)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶,—NSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl,—N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,—(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl, —(CO)(C₂-C₉)heterocyclyl,—(CO)(C₁-C₉)heteroaryl, —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,—(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl, —(CO)O(C₁-C₉)heteroaryl,—(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂, SO₂NH(C₁-C₆)alkyl,—SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and—SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₃-C₁₀)cycloalkyl,—(C₂-C₈)heterocyclyl, and —(C₁-C₆)alkyl—(C₂-C₉)heterocyclyl areoptionally interrupted by one to three elements selected from the groupconsisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR⁵; and R⁵ and R⁶of said NR⁵R⁶R³(b) group may be taken together with the atoms to whichthey are attached to form a —(C₂-C₉)heterocyclyl.

Also provided is a compound in which R³ is —(C₃-C₁₀)cycloalkyl,optionally substituted by one to three moieties independently selectedfrom the group consisting of halogen, hydroxy, —(C₁-C₆)alkyl,—(C₃-C₁₀)cycloalkyl, —NSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl,—N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂NH₂,SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶.

The invention further provides a compound in which R³ is—(C₂-C₈)heterocyclyl, optionally substituted by one to three moietiesindependently selected from the group consisting of halogen, hydroxy,—(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl, —NSO₂(C₁-C₆)alkyl,—NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂NH₂,SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶.

The invention further provides a compound in which R³ is—(C₁-C₆)alkyl—(C₂-C₉) heterocyclyl, optionally substituted by one tothree moieties independently selected from the group consisting ofhalogen, hydroxy, —(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl, —NSO₂(C₁-C₆)alkyl,—NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂NH₂,SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶.

Moreover, the invention provides a compound of formula 1 wherein R³ is—(C₁-C₆)alkyl optionally substituted by one to three moieties selectedfrom the group consisting of halogen, hydroxy, —(C₁-C₆)alkyl,—(C₁-C₆)alkyl-P(O)(O(C₁-C₆)alkyl)₂, —(C₃-C₁₀)cycloalkyl, (C₆-C₁₀)aryl,(C₂-C₉)heterocyclyl, —(C₁-C₉)heteroaryl, —NR⁵R⁶, —NSO₂(C₁-C₆)alkyl,—NHSO₂(C₃-C₆)cycloalkyl, —N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —(CO)(C₁-C₆)alkyl, —(CO)CF₃,—(CO)(C₃-C₁₀)cycloalkyl, —(CO)(C₆-C₁₀)aryl, —(CO)(C₂-C₉)heterocyclyl,—(CO)(C₁-C₉)heteroaryl, —(CO)O(C₁-C₆)alkyl, —(CO)O(C₃-C₁₀)cycloalkyl,—(CO)O(C₆-C₁₀)aryl, —(CO)O(C₂-C₉)heterocyclyl, —(CO)O(C₁-C₉)heteroaryl,—(CO)(C₁-C₆)alkyl-O(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl,—SO₂(C₃-C₆)cycloalkyl, SO₂CF₃, SO₂NH₂, SO₂NH(C₁-C₆)alkyl,—SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, —SO₂NR⁵R⁶, and—SO₂N(C₁-C₆)alkyl—(C₆-C₁₀)aryl; wherein said —(C₁-C₆)alkyl is optionallyinterrupted by one to three elements selected from the group consistingof —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR⁵; and R⁵ and R⁶ of saidNR⁵R⁶R³(b) group may be taken together with the atoms to which they areattached to form a —(C₂-C₉)heterocyclyl.

Further provided is a compound of formula 1 wherein R³ is —(C₁-C₆)alkyloptionally substituted by one to three moieties selected from the groupconsisting of halogen, hydroxy, —(C₁-C₆)alkyl, —(C₃-C₁₀)cycloalkyl,—NSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl,—N((C₁-C₆)alkyl)(SO₂—C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, —SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, —SO₂NH₂,SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶.

In a preferred embodiment, R⁴ is a substituent selected from the groupconsisting of hydrogen, (C₁-C₆)alkyl, and —(C₃-C₇)cycloalkyl; whereinsaid —(C₁-C₆)alkyl and —(C₃-C₇)cycloalkyl is optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, —(C₁-C₆)alkyl, —CN, —NR⁵ ₂, —OR⁵,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, and —CONR⁵R⁸; with theproviso that a heteroatom of the foregoing R⁴ substituents may not bebound to an sp³ carbon atom bound to another heteroatom; and wherein R⁵and R⁸ of said —CONR⁵R⁸ group may be taken together with the atoms towhich they are attached to form a —(C₂-C₉)heterocyclyl.

In a further preferred embodiment, R⁴ is hydrogen.

Further, the invention provides a compound of formula 1 wherein R⁵ andR⁶ are each substituents independently selected from the groupconsisting of hydrogen and —(C₁-C₆)alkyl, optionally substituted asdescribed above.

In a preferred embodiment, the present invention provides a compound ofthe formula 2

wherein A is selected from the group consisting of:

wherein m is an integer from 0-3 and R¹³ is a substituent selected fromthe group consisting of hydrogen, halogen, hydroxy, (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, (C₆-C₁₀)-aryl, (C₁-C₉)heteroaryl,(C₂-C₉)-heterocyclyl, O—(C₁-C₆)-alkyl, O—(C₃-C₇)-cycloalkyl,SO₂—(C₁-C₆)alkyl, SO₂(C₃-C₇)-cycloalkyl, NHSO₂(C₁-C₆)alkyl,N((C₁-C₆)alkyl)(SO₂(C₁-C₆-alkyl)),N((C₃-C₇)cycloalkyl)(SO₂(C₁-C₆-alkyl)),N(C₁-C₆-alkyl)(SO₂(C₃-C₇)cycloalkyl),N((C₃-C₇)cycloalkyl)(SO₂(C₃-C₇)cycloalkyl), OSO₂(C₁-C₆)alkyl, SO₂CF₃,SO₂NH₂, SO₂NH(C₁-C₆)alkyl, SO₂NH(C₃-C₇)cycloalkyl, SO₂NR⁵R⁶,SO₂N((C₁-C₆)alkyl)₂, CF₃, CO—(C₁-C₆)alkyl, CO—(C₃-C₇)cycloalkyl, COCF₃,CO₂(C₁-C₆)alkyl,

Also provided is a compound of the formula 3

wherein B is selected from the group consisting of:

The present invention also provides a compound of formula 4

wherein D is selected from the group consisting of:

wherein q is an integer from 1-2.

Moreover, the present invention provides a compound of formula 5:

wherein E is selected from the group consisting of:

wherein R¹⁴ is selected from the group consisting of (C₁-C₆)-alkyl,(C₃-C₇)-cycloalkyl, and (C₂-C₉)-heterocyclyl, and R¹⁵ is selected fromthe group consisting of hydrogen, (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl, and(C₂-C₉)-heterocyclyl.

Specific embodiments of the present invention are compounds selectedfrom

-   N-(1-Methyl-1-phenyl-ethyl)-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   5-{4-[3-(Trifluoro-methanesulfonyl)-benzylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   3-Oxo-3-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-piperidin-1-yl)-propionitrile;-   5-{4-[3-(1,1-Dioxo-1N⁶-isothiazolidin-2-yl)-propylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Methyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-piperidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-{2-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   N-{4-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-butyl}-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-piperidin-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;

Methanesulfonic acid3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenylester;

-   N-{3-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[(4-Methanesulfonyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(5-Oxo-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one-   N-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Trifluoroacetyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-azetidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   {2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-carbamic    acid tert-butyl ester;-   5-[4-(3-Isopropoxy-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Tetrahydro-pyran-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Ethyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5{-4-[(Tetrahydro-furan-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Tetrahydro-furan-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(5-Methyl-furan-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Adamantan-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Adamantan-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Methoxy-2-methyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(endo-Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   (3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzyl)-phosphonic    acid dimethyl ester;-   5-[4-(3-Methyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(2-Hydroxy-cyclohexylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   5-{4-[(4-Ethanesulfonyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-(4-{[4-(Propane-2-sulfonyl)-morpholin-2-ylmethyl]-amino}-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-{4-[(4-Acetyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Propionyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-(4-{[4-(2,2-Dimethyl-propionyl)-morpholin-2-ylmethyl]-amino}-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   2-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-morpholine-4-carboxylic    acid methyl ester;-   5-{4-[(4-Methoxyacetyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Ethanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(4-Methanesulfonyl-morpholin-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Methanesulfonyl-morpholin-2    S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Pyrimidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Pyrazin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Isobutyryl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3,3-Dimethyl-2-oxo-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1,2-Dimethyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(2-Methoxy-1-methyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[2-(1,1-Dioxo-1D⁶-isothiazolidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Methylamino-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(Pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[3-(1,1-Dioxo-1,1,6-isothiazolidin-2-yl)-benzylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(1R-Phenyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-(4-Isopropylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-(4R-sec-Butylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-(4S-sec-Butylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-[4-(2-Methylamino-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1S-Phenyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(2-Methanesulfonylmethyl-thiazol-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-(4-Propylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-[4-(2-Hydroxy-1-methyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1-Hydroxymethyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Pyridin-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(1,3-Dimethyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-[4-(1S-Hydroxymethyl-2-methyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Cyclohexyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-[4-(1,2,3,4-Tetrahydro-naphthalen-1-ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(3-Methyl-thiophen-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-3R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Hydroxy-1S-phenyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(2-Hydroxy-1S-methyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1R-Hydroxymethyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1-Pyrimidin-4-yl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1,1-Dioxo-tetrahydro-1-thiophen-3-ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1H-Imidazol-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Piperidin-2-yl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(Isobutyl-methyl-amino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-[4-(2-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Isopropyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Pyrimidin-2-yl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2R-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2S-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Methylsulfanyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1S-Hydroxymethyl-3-methylsulfanyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(2-Hydroxy-1R-methyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1R-Hydroxymethyl-2-methyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-3R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(1S-Hydroxymethyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(3,5-Dinitro-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Isopropyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   5-[4-(2-Hydroxy-1-phenyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1R-Hydroxymethyl-3-methyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(1S-Hydroxymethyl-3-methyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-piperidin-2S-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-2R-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(Methyl-pyridin-2-ylmethyl-amino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(3-Methanesulfonyl-benzyl)-methyl-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-[4-(Methyl-pyridin-3-ylmethyl-amino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-methyl-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(Methyl-pyridin-4-ylmethyl-amino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-(4-Cyclopentylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-[4-(2,6-Dimethoxy-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one    and    [4-(2-Imidazol-1-yl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one.

Certain preferred embodiments of the invention are compounds selectedfrom:

-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Methyl-butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   N-Cyclohexyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Isopropyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-(4-Cyclopentylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   Ethanesulfonic acid    methyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide;-   2,2,2-Trifluoro-N-methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-acetamide;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   5-(4-Cyclobutylamino-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one;-   5-{4-[2-Hydroxy-2-(1-methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   3-Oxo-3-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-piperidin-1-yl)-propionitrile;-   5-{4-[(1-Methanesulfonyl-piperidin-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Methanesulfonyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(5-Oxo-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Isopropoxy-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(Adamantan-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[(1-Hydroxy-cyclopentylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Hydroxy-tetrahydro-pyran-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(2-Hydroxy-cyclohexylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Methanesulfonyl-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Pyrimidin-2-yl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   3-[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propionic    acid ethyl ester;-   5-{4-[(1-Ethyl-5-oxo-pyrrolidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   2,N-Dimethyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-butyramide;-   2-Methoxy-N-methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-acetamide;-   5-{4-[2-(1-Acetyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-piperidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1-Pyrimidin-2-yl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-[4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(5-Methyl-furan-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   (3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzyl)-phosphonic    acid dimethyl ester;-   5-{4-[(Pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[5-Trifluoromethyl-4-(2-trifluoromethyl-benzylamino)-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-[4-(3-Ethanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(Pyrimidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Pyrazin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   5-{4-[(Pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(2-Methanesulfonylmethyl-thiazol-4-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(3-Methyl-thiophen-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(1H-Imidazol-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-[4-(2-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(1,5-Dimethyl-1H-pyrazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Imidazol-1-yl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   N-(5-Methyl-2-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(3-Methyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(Isochroman-1-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(Pyridin-3-yloxy)-propylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(6-Methyl-pyridin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(2,3-Dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(4-Methyl-1H-imidazol-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(1H-Benzoimidazol-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(5-Phenyl-4H-[1,2,4]triazol-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(3-Methyl-imidazo[2,1-b]thiazol-6-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(2-Methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-(3-Methanesulfonylamino-5-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;    and-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide.

Preferred embodiment of the present invention are selected from5-[4-(3-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;

Ethanesulfonic acidmethyl-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-amide;

-   5-{4-[(Isochroman-1-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(Pyridin-3-yloxy)-propylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide;-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide;-   5-{4-[(4-Methanesulfonyl-morpholin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Methanesulfonylmethyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide;-   5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(4-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(3-Isopropoxy-propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(5-Methyl-furan-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(Bicyclo[2.2.1]hept-5-en-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(6-Methanesulfonyl-pyridin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[(5-Methanesulfonyl-pyridin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-[4-(2-Methanesulfonyl-benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Pyrimidin-2-yl-piperidin-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-{4-[(1-Methanesulfonyl-pyrrolidin-2-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   N-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   N-Methyl-N-(2-methyl-6-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide;-   5-[4-(2-Hydroxy-indan-1-ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one;-   5-{4-[(1-Hydroxy-cyclopentylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;-   5-{4-[2-Hydroxy-2-(1-methanesulfonyl-piperidin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one;    and-   N-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal, including a human, comprising administering tosaid mammal an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth. In one embodiment of thismethod, the abnormal cell growth is cancer, including, but not limitedto, lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer ofthe head or neck, cutaneous or intraocular melanoma, uterine cancer,ovarian cancer, rectal cancer, cancer of the anal region, stomachcancer, colon cancer, breast cancer, uterine cancer, carcinoma of thefallopian tubes, carcinoma of the endometrium, carcinoma of the cervix,carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease,cancer of the esophagus, cancer of the small intestine, cancer of theendocrine system, cancer of the thyroid gland, cancer of the parathyroidgland, cancer of the adrenal gland, sarcoma of soft tissue, cancer ofthe urethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In one embodimentthe method comprises comprising administering to a mammal an amount of acompound of formula I that is effective in treating said cancer solidtumor. In one preferred embodiment the solid tumor is breast, lung,colon, brain, prostate, stomach, pancreatic, ovarian, skin (melanoma),endocrine, uterine, testicular, and bladder cancer.

In another embodiment of said method, said abnormal cell growth is abenign proliferative disease, including, but not limited to, psoriasis,benign prostatic hypertrophy or restinosis.

This invention also relates to a method for the treatment of abnormalcell growth in a mammal which comprises administering to said mammal anamount of a compound of formula 1, or a pharmaceutically acceptablesalt, solvate or prodrug thereof, that is effective in treating abnormalcell growth in combination with an anti-tumor agent selected from thegroup consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, antibodies, cytotoxics, anti-hormones, andanti-androgens.

This invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1, as defined above,or a pharmaceutically acceptable salt, solvate or prodrug thereof, thatis effective in treating abnormal cell growth, and a pharmaceuticallyacceptable carrier. In one embodiment of said composition, said abnormalcell growth is cancer, including, but not limited to, lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancers. In anotherembodiment of said pharmaceutical composition, said abnormal cell growthis a benign proliferative disease, including, but not limited to,psoriasis, benign prostatic hypertrophy or restinosis.

The invention also relates to a pharmaceutical composition for thetreatment of abnormal cell growth in a mammal, including a human, whichcomprises an amount of a compound of formula 1, as defined above, or apharmaceutically acceptable salt, solvate or prodrug thereof, that iseffective in treating abnormal cell growth in combination with apharmaceutically acceptable carrier and an anti-tumor agent selectedfrom the group consisting of mitotic inhibitors, alkylating agents,anti-metabolites, intercalating antibiotics, growth factor inhibitors,cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologicalresponse modifiers, anti-hormones, and anti-androgens.

This invention also relates to a method for the treatment of a disorderassociated with angiogenesis in a mammal, including a human, comprisingadministering to said mammal an amount of a compound of the formula 1,as defined above, or a pharmaceutically acceptable salt, solvate orprodrug thereof, that is effective in treating said disorder. Suchdisorders include cancerous tumors such as melanoma; ocular disorderssuch as age-related macular degeneration, presumed ocular histoplasmosissyndrome, and retinal neovascularization from proliferative diabeticretinopathy; rheumatoid arthritis; bone loss disorders such asosteoporosis, particularly, post-menopausal osteoporosis, Paget'sdisease, humoral hypercalcemia of malignancy, hypercalcemia from tumorsmetastatic to bone, and osteoporosis induced by glucocorticoidtreatment; coronary restenosis; and certain microbial infectionsincluding those associated with microbial pathogens selected fromadenovirus, hantaviruses, Borrelia burgdorferi, Yersinia spp.,Bordetella pertussis, and group A Streptococcus.

This invention also relates to a method of (and to a pharmaceuticalcomposition for) treating abnormal cell growth in a mammal whichcomprise an amount of a compound of formula 1, or a pharmaceuticallyacceptable salt, solvate or prodrug thereof, and an amount of one ormore substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents, which amounts aretogether effective in treating said abnormal cell growth.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloprotienase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of formula 1 in the methods and pharmaceutical compositionsdescribed herein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931,788 (published Jul. 28, 1999), WO90/05719 (published May 331, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain patent application number 9912961.1 (filed Jun.3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are herein incorporatedby reference in their entirety. Preferred MMP-2 and MMP-9 inhibitors arethose that have little or no activity inhibiting MMP-1. More preferred,are those that selectively inhibit MMP-2 and/or MMP-9 relative to theother matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in combination with thecompounds of the present invention are AG-3340, RO 32-3555, RS 13-0830,and the compounds recited in the following list:

-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic    acid;-   3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   (2R,3R)    1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic    acid;-   4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic    acid hydroxyamide;-   (2R,3R)    1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic    acid;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic    acid;-   3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide; and-   3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic    acid hydroxyamide;

and pharmaceutically acceptable salts, solvates and prodrugs of saidcompounds.

The compounds of formula 1, and the pharmaceutically acceptable salts,solvates and prodrugs thereof, can also be used in combination withsignal transduction inhibitors, such as agents that can inhibit EGFR(epidermal growth factor receptor) responses, such as EGFR antibodies,EGF antibodies, and molecules that are EGFR inhibitors; VEGF (vascularendothelial growth factor) inhibitors; and erbB2 receptor inhibitors,such as organic molecules or antibodies that bind to the erbB2 receptor,for example, HERCEPTIN™ (Genentech, Inc. of South San Francisco, Calif.,USA).

EGFR inhibitors are described in, for example in WO 95/19970 (publishedJul. 27, 1995), WO 98/14451 (published Apr. 9, 1998), WO 98/02434(published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5,1998). EGFR-inhibiting agents include, but are not limited to, CI-1033(Pfizer Inc.), the monoclonal antibodies C225 and anti-EGFR 22Mab(ImClone Systems Incorporated of New York, N.Y., USA), the compoundsZD-1839 (AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447(Medarex Inc. of Annandale, N.J., USA), and OLX-103 (Merck & Co. ofWhitehouse Station, N.J., USA), VRCTC-3 10 (Ventech Research) and EGFfusion toxin (Seragen Inc. of Hopkinton, Massachusettes).

VEGF inhibitors, for example CP-547,632 and AG-13736 (Pfizer, Inc.),SU-5416 and SU-6668 (Sugen Inc. of South San Francisco, Calif., USA),can also be combined with a compound of formula 1. VEGF inhibitors aredescribed in, for example in WO 99/24440 (published May 20, 1999), PCTInternational Application PCT/IB99/00797 (filed May 3, 1999), in WO95/21613 (published Aug. 17, 1995), WO 99/61422 (published Dec. 2,1999), U.S. Pat. No. 5,834,504 (issued Nov. 10, 1998), WO 98/50356(published Nov. 12, 1998), U.S. Pat. No. 5,883,113 (issued Mar. 16,1999), U.S. Pat. No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No.5,792,783 (issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999),WO 97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26,1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published Jan.22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO 98/02437(published Jan. 22, 1998), all of which are herein incorporated byreference in their entirety. Other examples of some specific VEGFinhibitors are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGFmonoclonal antibody of Genentech, Inc. of South San Francisco, Calif.;and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) andChiron (Emeryville, Calif.).

ErbB2 receptor inhibitors, such as CP-724,714 (Pfizer, Inc.), GW-282974(Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (AronexPharmaceuticals Inc. of The Woodlands, Tex., USA) and 2B-1 (Chiron), maybe administered in combination with a compound of formula 1. Such erbB2inhibitors include those described in WO 98/02434 (published Jan. 22,1998), WO 99/35146 (published Jul. 15, 1999), WO 99/35132 (publishedJul. 15, 1999), WO 98/02437 (published Jan. 22, 1998), WO 97/13760(published Apr. 17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S.Pat. No. 5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305(issued Mar. 2, 1999), each of which is herein incorporated by referencein its entirety. ErbB2 receptor inhibitors useful in the presentinvention are also described in U.S. Provisional Application No.60/117,341, filed Jan. 27, 1999, and in U.S. Provisional Application No.60/117,346, filed Jan. 27, 1999, both of which are herein incorporatedby reference in their entirety.

Other antiproliferative agents that may be used with the compounds ofthe present invention include inhibitors of HDI (CI-994, Pfizer Inc.),MEK (CI-1040, Pfizer Inc.), the enzyme farnesyl protein transferase andthe receptor tyrosine kinase PDGFr, including the compounds disclosedand claimed in the following U.S. patent application Ser Nos. 09/221,946(filed Dec. 28, 1998); 09/454,058 (filed Dec. 2, 1999); 09/501,163(filed Feb. 9, 2000); 09/539,930 (filed Mar. 31, 2000); 09/202,796(filed May 22, 1997); 09/384,339 (filed Aug. 26, 1999); and 09/383,755(filed Aug. 26, 1999); and the compounds disclosed and claimed in thefollowing United States provisional patent applications: 60/168,207(filed Nov. 30, 1999); 60/170,119 (filed Dec. 10, 1999); 60/177,718(filed Jan. 21, 2000); 60/168,217 (filed Nov. 30, 1999), and 60/200,834(filed May 1, 2000). The compounds of the invention may also be used incombination with inhibitors of topoisomerase I, e.g., irinotecan(Camptosar®) and edotecarin. Each of the foregoing patent applicationsand provisional patent applications is herein incorporated by referencein their entirety.

A compound of formula 1 may also be used with other agents useful intreating abnormal cell growth or cancer, including, but not limited to,agents capable of enhancing antitumor immune responses, such as CTLA4(cytotoxic lymphocite antigen 4) antibodies, and other agents capable ofblocking CTLA4; and anti-proliferative agents such as other farnesylprotein transferase inhibitors, for example the farnesyl proteintransferase inhibitors described in the references cited in the“Background” section, supra. Specific CTLA4 antibodies that can be usedin the present invention include those described in U.S. ProvisionalApplication 60/113,647 (filed Dec. 23, 1998) which is hereinincorporated by reference in its entirety.

“Abnormal cell growth”, as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes theabnormal growth of: (1) tumor cells (tumors) that proliferate byexpressing a mutated tyrosine kinase or overexpression of a receptortyrosine kinase; (2) benign and malignant cells of other proliferativediseases in which aberrant tyrosine kinase activation occurs; (4) anytumors that proliferate by receptor tyrosine kinases; (5) any tumorsthat proliferate by aberrant serine/threonine kinase activation; and (6)benign and malignant cells of other proliferative diseases in whichaberrant serine/threonine kinase activation occurs.

The compounds of the present invention are potent inhibitors of the FAKprotein tyrosine kinases, and thus are all adapted to therapeutic use asantiproliferative agents (e.g., anticancer), antitumor (e.g., effectiveagainst solid tumors), antiangiogenesis (e.g., stop or preventproliferationation of blood vessels) in mammals, particularly in humans.In particular, the compounds of the present invention are useful in theprevention and treatment of a variety of human hyperproliferativedisorders such as malignant and benign tumors of the liver, kidney,bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic,lung, vulval, thyroid, hepatic carcinomas, sarcomas, glioblastomas, headand neck, and other hyperplastic conditions such as benign hyperplasiaof the skin (e.g., psoriasis) and benign hyperplasia of the prostate(e.g., BPH). It is, in addition, expected that a compound of the presentinvention may possess activity against a range of leukemias and lymphoidmalignancies.

In one preferred embodiment of the present invention cancer is selectedfrom lung cancer, bone cancer, pancreatic cancer, gastric, skin cancer,cancer of the head or neck, cutaneous or intraocular melanoma, uterinecancer, ovarian cancer, gynecological, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, uterine cancer,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina, carcinoma of thevulva, Hodgkin's Disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system, cancer of the thyroid gland,cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma ofsoft tissue, cancer of the urethra, cancer of the penis, squamous cell,prostate cancer, chronic or acute leukemia, lymphocytic lymphomas,cancer of the bladder, cancer of the kidney or ureter, renal cellcarcinoma, carcinoma of the renal pelvis, neoplasms of the centralnervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain,pituitary adenoma, or a combination of one or more of the foregoingcancers.

In a more preferred embodiment cancer is selected a solid tumor, suchas, but not limited to, breast, lung, colon, brain, prostate, stomach,pancreatic, ovarian, skin (melanoma), endocrine, uterine, testicular,and bladder.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, unless otherwise indicated, refers to the act of treating as“treating” is defined immediately above.

The present invention also provides a pharmaceutical compositioncomprising a compound of formula (I), or a pharmaceutically acceptablesalt or solvate thereof, as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I), or a pharmaceutically acceptable salt orsolvate thereof, as hereinbefore defined with a pharmaceuticallyacceptable adjuvant, diluent or carrier.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 1 mg to 1 gram, preferably 1 mg to 250 mg, morepreferably 10 mg to 100 mg.

The present invention also encompasses sustained release compositions.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula 1 can be prepared using the synthetic routeoutlined in Scheme 1. The substituents in Scheme 1 have the same meaningas the substituents defined for formula 1.

Compounds of formula 1 can be prepared starting from the5-amino-oxindole (2) and pyrimidine (3). Combining 3 with an equimolaramount of a Lewis Acid at temperatures ranging from −15 to 45° C. for atime period of 10-60 minutes in an inert solvent (or solvent mixture)followed by addition of 2 and a suitable base provides after the periodof 1-24 h the intermediate 4-chloropyrimidine (4) in high yields.Examples of inert solvents include but are not limited to THF,1,4-dioxane, n-BuOH, i-PrOH, dichloromethane and 1,2-dichloroethane.Examples of suitable bases employed may include but are not limited to(i) non-nucleophilic organic bases for example triethylamine ordiisopropylethylamine (ii) inorganic bases such as potassium carbonateor cesium carbonate or (iii) resin bound bases such as MP-carbonate.

Examples of Lewis Acids include but are not limited to halide salts ofmagnesium, copper, zinc, tin or titanium. In the next reaction,intermediate 4 is reacted with an amine of the formula 5 either neat orin the presence of an inert solvent (or solvent mixture) at temperaturesranging from 0 to 150° C. to provide the compounds of formula 1.Optionally this reaction can be run in the presence of a suitable base.Examples of suitable solvents for this reaction include but are notlimited to THF, 1,4-dioxane, DMF, N-methyl-pyrrolidinone, EtOH, n-BuOH,i-PrOH, dichloromethane, 1,2-dichloroethane, DMSO or acetonitrile.Suitable bases are as outlined above.

Compounds of the present invention may be synthetically transformed intoother compounds of the invention by techniques known to those skilled inthe art. Simply for illustrative purposes and without limitation, suchmethods include:

a) removal of a protecting group by methods outlined in T. W. Greene andP. G. M. Wuts, “Protective Groups in Organic Synthesis”, Second Edition,John Wiley and Sons, New York, 1991; e.g., emoval of a BOC protectinggroup with an acid source such as HCl or trifluoroacetic acid.

b) displacement of a leaving group (halide, mesylate, tosylate, etc)with functional groups such as but not limited to a primary or secondaryamine, thiol or alcohol to form a secondary or tertiary amine, thioetheror ether, respectively.

c) treatment of phenyl (or substituted phenyl) carbamates with primaryof secondary amines to form the corresponding ureas as in Thavonekham, Bet. al. Synthesis (1997), 10, p1189;

d) reduction of propargyl or homopropargyl alcohols or N—BOC protectedprimary amines to the corresponding E-allylic or E-homoallylicderivatives by treatment with sodium bis(2-methoxyethoxy)aluminumhydride (Red-Al) as in Denmark, S. E.; Jones, T. K. J. Org. Chem. (1982)47, 4595-4597 or van Benthem, R. A. T. M.; Michels, J. J.; Speckamp, W.N. Synlett (1994), 368-370;

e) reduction of alkynes to the corresponding Z-alkene derivatives bytreatment hydrogen gas and a Pd catalyst as in Tomassy, B. et. al.Synth. Commun. (1998), 28, p1201

f) treatment of primary and secondary amines with an isocyanate, acidchloride (or other activated carboxylic acid derivative), alkyl/arylchloroformate or sulfonyl chloride to provide the corresponding urea,amide, carbamate or sulfonamide;

g) reductive amination of a primary or secondary amine using an aldehydeor ketone and an appropriate reducing reagent.

h) treatment of alcohols with an isocyanate, acid chloride (or otheractivated carboxylic acid derivative), alkyl/aryl chloroformate orsulfonyl chloride to provide the corresponding carbamate, ester,carbonate or sulfonic acid ester.

Amines of the formula 5 may be purchased and used directly oralternatively be prepared by one skilled in the art using ordinarychemical transformations. For example; arylalkylamines orheteroarylalkylamines may be prepared from the corresponding nitrile bycatalytic hydrogenation using catalysts such as Pd/C or Raney Nickel orby lithium aluminum hydride reduction, (see Rylander, CatalyticHydrogenation in Organic Synthesis, Academic Press, 1979).

The nitrile starting materials can be either purchased or prepared fromthe corresponding arylvheteroaryl bromide, iodide or triflate andZn(CN)₂ using Pd coupling conditions found in Tschaen, D. M., et. alSynthetic Communications (1994), 24, 6, pp 887-890.

Alternatively, benzylamines or heteroarylmethylamines can be prepared byreacting the appropriate arylalkyl or heteroarylalkyl halide and thepotassium salt of (BOC)₂NH (reference) and subsequent removal of the BOCgroups with acid.

Amines, protected forms of amines, precursors to amines and precursorsto the protected forms of amines of formula 5 can be prepared bycombining the appropriate alkyne, or alkenyl stannane, alkenyl borane,alkenyl boronic acid, boronic ester with the appropriate aryl orheteroaryl bromide, iodide or triflate using Pd coupling conditions asfound in Tsuji, J.; Palladium Reagents and Catalysis, John Wiley andSons 1999 and references cited therein.

Appropriately protected amines of formula 5 may be converted todifferent amines of formula 5 according to methods familiar to thoseskilled in the art for exampleas but limited to:

(a) oxidation of a thioether to a sulfoxide or sulfone.

(b) N-alkylation of a sulfanilide can be achieved under phase transferusing conditions described by Brehme, R. “Synthesis”, (1976), ppl13-114.

As understood by those skilled in the art, the chemical transformationto convert an aryl halide or triflate or heteroaryl halide or triflateto an aromatic or heteroaromatic amine may be carried out usingconditions currently outlined in the literature, see Hartwig, J. F.:“Angew. Chem. Int. Ed.” (1998), 37, pp. 2046-2067, Wolfe, J. P.; Wagaw,S.; Marcoux, J. F.; Buchwald, S. L.; “Acc. Chem. Res.”, (1998), 31, pp805-818, Wolfe, J. P.; Buchwald, S. L.; “J. Org. Chem.”, (2000), 65, pp1144-1157, Muci, A. R.; Buchwald, S. L.; “Topics in Current Chemistry”(2002), pp 131-209 and references cited therein. Further, as understoodby those skilled in the art, these same aryl or heteroaryl aminatiionchemical transformations may alternatively be carried out on nitrile (orprimary amide) precursors which provide amines of the formula 5 afternitrile (or amide) reduction. Protected amines of formula 5 may befurther converted to different amines of formula 5 according to methodsfamiliar to those skilled in the art.

The in vitro activity of the compounds of formula I may be determined bythe following procedure. More particularly, the following assay providesa method to determine whether compounds of the formula 1 inhibit thetyrosine kinase activity of the catalytic construct FAK(410-689). Theassay is an ELISA-based format, measuring the inhibition of poly-glu-tyrphosphorylation by FAK(410-689).

The assay protocol has three parts:

I. Purification and cleavage of His-FAK(410-689)

II. FAK410-689 (a.k.a. FAKcd) Activation

III. FAKcd Kinase ELISA

Materials:

-   -   Ni-NTA agarose (Qiagen)    -   XK-16 column (Amersham-Pharmacia)    -   300 mM Imidizole    -   Superdex 200 HiLoad 16/60 prep grade column (Amersham Biotech.)    -   Antibody: Anti-Phosphotyrosine HRP-Conjugated Py20 (Transduction        labs).    -   FAKcd: Purified and activated in house    -   TMB Microwell Peroxidase Substrate (Oncogene Research Products        #CL07)    -   BSA: Sigma #A3294    -   Tween-20: Sigma #P1379    -   DMSO: Sigma #D-5879    -   D-PBS: Gibco #14190-037.

Reagents for Purification:

-   -   Buffer A: 50 mM HEPES pH 7.0,    -   500 mM NaCl,    -   0.1 mM TCEP    -   Complete™ protease inhibitor cocktail tablets (Roche)    -   Buffer B: 25 mM HEPES pH 7.0,    -   400 mM NaCl    -   0.1 mM TCEP.    -   Buffer C: 10 mM HEPES pH 7.5,    -   200 mM Ammonium Sulfate    -   0.1 mM TCEP.

Reagents for Activation

-   -   FAK(410-689): 3 tubes of frozen aliquots at 150 ul/tube for a        total of 450 ul at 1.48 mg/ml (660 ug)    -   His-Src(249-524): 0.74 mg/ml stock in 10 mM HEPES, 200 mM        (NH₄)₂SO₄    -   Src reaction buffer (Upstate Biotech):        -   100 mM Tris-HCl pH7.2,        -   125 mM MgCl₂,        -   25 mM MnCl₂,        -   2 mM EDTA,        -   250 uM Na3VO4,        -   2 mMDTT    -   Mn2+/ATP cocktail (Upstate Biotech)        -   75 mM MnC12        -   500 uM ATP        -   20 mM MOPS pH 7.2        -   1 mM Na3VO4        -   25 mM □-glycerol phosphate        -   5 mM EGTA        -   1 mM DTT    -   ATP: 150 mM stock    -   MgCl₂: 1 M Stock    -   DTT: IM stock

Reagents for FAKcd Kinase ELISA

-   -   Phosphorylation Buffer:        -   50 mM HEPES, pH 7.5,        -   125 mM NaCl,        -   48 mM MgCl₂    -   Wash Buffer: TBS+0.1% Tween-20.    -   Blocking Buffer:        -   Tris Buffer Saline,        -   3% BSA,        -   0.05% Tween-20, filtered.    -   Plate Coating Buffer:        -   50 mg/ml Poly-Glu-Tyr (Sigma #PO₂₇₅) in Phosphate buffer            Saline (DPBS).    -   ATP: 0.1M ATP in H₂O or HEPES, pH7.        -   Note: ATP Assay Buffer:        -   Make up as 75 uM ATP in PBS, so that 80 ul in        -   120 ul reaction volume=50 uM final ATP concentration.

I. Purification of His-FAKcd(410-689)

1. Resuspend 130 g baculovirus cell paste containing the over expressedHis-FAKcd410-689 recombinant protein in 3 volumes (400 ml) of Buffer A,

2. Lyse cells with one pass on a microfluidizer

3. Remove cell debris by centrifugation at 4OC for 35 minutes at 14,000rpm in a Sorval SLA-1500 rotor.

4. Transfer the supernatant to a clean tube and add 6.0 ml of Ni-NTAagarose (Qiagen)

5. Incubate the suspension with gentle rocking at 4OC for 1 hour

6. Centrifuge suspension at 700×g in a swinging bucket rotor.

7. Discard the supernatant and resuspend the agarose beads in 20.0 ml ofBuffer A

8. Transfer the beads to an XK-16 column (Amersham-Pharmacia) connectedto a FPLCTM.

9. Wash the agarose-beads with 5 column volumes of Buffer A and eluteoff the column with a step gradient of Buffer A containing 300 mMImidizole.

10. Perform a buffer exchange of the eluted fractions into Buffer B

11. Following buffer exchange, pool the fractions and add thrombin at a1:300 (w/w) ratio and incubated overnight at 13° C. to remove theN-terminal His-tag (His-FAK410-698→FAK410-689 (a.k.a. FAKcd)).

12. Add the reaction mixture back onto the Ni-NTA column equilibratedwith Buffer A and collect the flow-through.

13. Concentrate the flow-through down to 1.7 ml and load directly onto aSuperdex 200 HiLoad 16/60 prep grade column equilibrated with Buffer C.The desired protein elutes between 85-95 ml.

14. Aliquot the FAKcd protein and store frozen at −80° C.

II. FAK Activation

-   -   1. To 450 ul of FAK(410-689) at 1.48 mg/ml (660 ug) add the        following:        -   30 ul of 0.037 mg/ml (1 uM) His-Src(249-524)        -   30 ul of 7.5 mM ATP        -   12 ul of 20 mM MgCl₂        -   10 ul Mn2+/ATP cocktail (UpState Biotech.)        -   4 ul of 6.7 mM DTT        -   60 ul Src Reaction Buffer (UpState Biotech.)    -   2. Incubate Reaction for at least 3 hours at room temperature

At time t₀, almost all of the FAK(410-689) is singly phosphorylated. Thesecond phosphorylation is slow. At tl₂₀ (t=120 minutes), add 10 ul of150 mM ATP.

T₀=(Start) 90% singly phosphorylated FAK(410-689) (1 PO4)

T₄₃=(43 min) 65% singly phosphorylated (1 PO4), 35% doublyphosphorylated (2 PO4)

T₉₀=(90 min) 45% 1 PO4, 55% 2 PO4

T₁₅₀=15% 1 PO4, 85% 2 PO4

T₂₁₀=<10% 1 PO4, >90% 2 PO4 desalted sample

3. Add 180 ul aliquots of the desalted material to NiNTA spin column andincubate on spin column 4. Spin at 10 k rpm (microfuge), for 5 min toisolate and collect flow through (Activated FAK(410-689)) and removeHis-Src (captured on column)

III. FAKcd Kinase ELISA

1. Coat 96-well Nunc MaxiSorp plates with poly-glu-tyr (pGT) at 10ug/well: Prepare 10 ug/ml of pGT in PBS and aliquot 100 ul/well.Incubate the plates at 37° C. overnight, aspirate the supernatant, washthe plates 3 times with Wash Buffer, and flick to dry before storing at4° C.

2. Prepare compound stock solutions of 2.5 mM in 100% DMSO. The stocksare subsequently diluted to 60× of the final concentration in 100% DMSO,and diluted 1:5 in Kinase Phosphorylation Buffer.

3. Prepare a 75 uM working ATP solution in Kinase phosphorylationbuffer. Add 80 ul to each well for a final ATP concentration of 50 uM.

4. Transfer 10 ul of the diluted compounds (0.5 log serial dilutions) toeach well of the pGT assay plate, running each compound in triplicateson the same plate.

5. Dilute on ice, FAKcd protein to 1:1000 in Kinase PhosphorylationBuffer. Dispense 30 ul per well.

6. Note: Linearity and the appropriate dilution must be pre-determinedfor each batch of protein. The enzyme concentration selected should besuch that quantitation of the assay signal will be approximately 0.8-1.0at OD450, and in the linear range of the reaction rate.

7. Prepare both a No ATP control (noise) and a No Compound Control(Signal):

8. (Noise) One blank row of wells receives 10 ul of 1:5 dilutedcompounds in DMSO, 80 ul of Phosphorylation buffer (minus ATP), and 30ul FAKcd solution.

9. (Siganl) Control wells receive 10 ul of 1:5 diluted DMSO (minusCompound) in Kinase phosphorylation buffer, 80 ul of 75 uM ATP, and 30ul of 1:1000 FAKcd enzyme.

10. Incubate reaction at room temperature for 15 minutes with gentleshaking on a plate shaker.

11. Terminate the reaction by aspirating off the reaction mixture andwashing 3 times with wash buffer.

12. Dilute phospho-tyrosine HRP-conjugated (pY20HRP) antibody to 0.250ug/ml (1:1000 of Stock) in blocking buffer. Dispense 100 ul per well,and incubate with shaking for 30 min. at R.T.

13. Aspirate the supernatant and wash the plate 3 times with washbuffer.

14. Add 100 ul per well of room temperature TMB solution to initiatecolor development. Color development is terminated after approximately15-30 sec. by the addition of 100 ul of 0.09M H2SO4 per well.

15. The signal is quantitated by measurement of absorbance at 450 nm onthe BioRad microplate reader or a microplate reader capable of readingat OD450.

16. Inhibition of tyrosine kinase activity would result in a reducedabsorbance signal. The signal is typically 0.8-1.0 OD units. The valuesare reported as IC₅₀s, uM concentration.

FAK Inducible cell-based ELISA: Final Protocol Materials:

Reacti-Bind Goat Anti-Rabbit Plates 96-well (Pierce Product#15135ZZ(115.00 USD)

FAKpY397 rabbit polyclonal antibody (Biosource #44624 (315.00 USD)

ChromePure Rabbit IgG, whole molecule (Jackson Laboratories #001-000-003@60/25 mg USD)

UBI αFAK clone 2A7 mouse monoclonal antibody (Upstate#05-182 @289.00USD)

Peroxidase-conjugated AffiniPure Goat Anti-Mouse IgG (Jackson Labs#115-035-146 @95/1.5 ml USD)

SuperBlock TBS (Pierce Product#37535ZZ @99 USD)

Bovine Serum Albumin (Sigma #A-9647 @117.95/100 g USD)

TMB Peroxidase substrate (Oncogene Research Products #CL07-100 ml (40.00USD)

Na3VO4 Sodium Orthovanadate (Sigma #S6508 (43.95/50 g USD)

MTT substrate (Sigma # M-2128 (25.95/500 mg USD)

Growth Media: DMEM+10% FBS, P/S, Glu, 750 ug/ml Zeocin and 50 ug/mlHygromycin (Zeocin InVitrogen #R250-05 (725 USD and HygromyconInVitrogen #R220-05 (150 USD)

Mifepristone InVitrogen # H110-01 @125 USD

Complete™ EDTA-free Protease Inhibitor pellet Boehringer Mannheim#1873580

FAK cell-based Protocol for selectivity of kinase-dependentphosphoFAKY397

Procedure:

An inducible FAK cell-based assay in ELISA format for the screening ofchemical matter to identify tyrosine kinase specific inhibitors wasdeveloped. The cell-based assay exploits the mechanism of theGeneSwitch™ system (InVitrogen) to exogenously control the expressionand phosphorylation of FAK and the kinase-dependent autophosphorylationsite at residue Y397.

Inhibition of the kinase-dependent autophosphorylation at Y397 resultsin a reduced absorbance signal at OD450. The signal is typically 0.9 to1.5 OD450 units with the noise falling in the range of 0.08 to 0.1 OD450units. The values are reported as IC50s, uM concentration.

On day 1, grow A431•FAKwt in T175 flasks. On the day prior to runningthe FAK cell-assay, seed A431•FAKwt cells in growth media on 96-wellU-bottom plates. Allow cells to sit at 37° C., 5% CO2 for 6 to 8 hoursprior to FAK induction. Prepare Mifepristone stock solution of 10 uM in100% Ethanol. The stock solution is subsequently diluted to 10× of thefinal concentration in Growth Media. Transfer 10 ul of this dilution(final concentration of 0.1 nM Mifepristone) into each well. Allow cellsto sit at 37° C., 5% CO2 overnight (12 to 16 hours). Also, preparecontrol wells without Mifepristone induction of FAK expression andphosphorylation.

On day 2, coat Goat Anti-Rabbit plate(s) with 3.5 ug/ml ofphosphospecific FAKpY397 polyclonal antibody prepared in SuperBlock TBSbuffer, and allow plate(s) to shake on a plate shaker at roomtemperature for 2 hours. Optionally, control wells may be coated with3.5 ug/ml of control Capture antibody (Whole Rabbit IgG molecules)prepared in SuperBlock TBS. Wash off excess FAKpY397 antibody 3 timesusing buffer. Block Anti-FAKpY397 coated plate(s) with 200 ul per wellof 3% BSA/0.5% Tween Blocking buffer for 1 hour at room temperature onthe plate shaker. While the plate(s) are blocking, prepare compoundstock solutions of 5 mM in 100% DMSO. The stock solutions aresubsequently serially diluted to 10× of the final concentration in 100%DMSO. Make a 1:10 dilution using the 100× solution into growth media andtransfer 10 ul of the appropriate compound dilutions to each wellcontaining either the FAK induced or uninduced control A431 cells for 30minutes at 37° C., 5% CO2. Prepare RIPA lysis buffer (50 mM Tris-HCl,pH7.4, 1% NP-40, 0.25% Na-deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mMNa3VO4, 1 mM NaF, and one Complete™ EDTA-free protease inhibitor pelletper 50 ml solution). At the end of 30 minutes compound treatment, washoff compound 3 times using TBS-T wash buffer. Lyse cells with 100ul/well of RIPA buffer.

To the coated plate, remove blocking buffer and wash 3 times using TBS-Twash buffer. Using a 96-well automated microdispenser, transfer 100 ulof whole cell-lysate (from step 6) to the Goat Anti-Rabbit FAKpY397coated plate(s) to capture phosphoFAKY397 proteins. Shake at roomtemperature for 2 hours. Wash off unbound proteins 3 times using TBS-Twash buffer. Prepare 0.5 ug/ml (1:2000 dilution) of UBI αFAK detectionantibody in 3% BSA/0.5% Tween blocking buffer. Dispense 100 ul of UBIαFAK solution per well and shake for 30 minutes at room temperature.Wash off excess UBI αFAK antibody 3 times using TBS-T wash buffer.Prepare 0.08 ug/ml (1:5000 dilution) of secondary Anti-Mouse Peroxidase(Anti-2 MHRP) conjugated antibody. Dispense 100 ul per well of theAnti-2 MHRP solution and shake for 30 minutes at room temperature. Washoff excess Anti-2 MHRP antibody 3 times using TBS-T wash buffer. Add 100ul per well of room temperature TMB substrate solution to allow forcolor development. Terminate the TMB reaction with 100 ul per well ofTMB stop solution (0.09M H2SO4) and quantitate the signal by measurementof absorbance at 450 nm on the BioRad microplate reader.

Additional FAK cell assays are hereby incorporated by reference fromPfizer Attorney Docket No. PC11699 entitled “INDUCIBLE FOCAL ADHESIONKINASE CELL ASSAY”.

In a preferred embodiment, the compounds of the present invention havean in vivo activity as determined by a kinase assay, e.g., such as thatdescribed herein, of less than 100 nM. Preferably, the compounds have anIC₅₀ of less than 25 nM in the kinase assay, and more preferably lessthan 10 nM. In a further preferred embodiment, the compounds exhibit anIC₅₀ in a FAK cell based assay, e.g., such as that described herein, ofless than 1 □M, more preferably less than 100 nM, and most preferablyless than 25 nM.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration, the disposition of the compound and thediscretion of the prescribing physician. However, an effective dosage isin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 1 to about 35 mg/kg/day, in single or divided doses.For a 70 kg human, this would amount to about 0.05 to about 7 g/day,preferably about 0.2 to about 2.5 g/day. In some instances, dosagelevels below the lower limit of the aforesaid range may be more thanadequate, while in other cases still larger doses may be employedwithout causing any harmful side effect, provided that such larger dosesare first divided into several small doses for administration throughoutthe day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex□ (tamoxifen) or, for example anti-androgens such as Casodex□(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trifluoromethyl)propionanilide).Such conjoint treatment may be achieved by way of the simultaneous,sequential or separate dosing of the individual components of thetreatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. In the following examples moleculeswith a single chiral center, unless otherwise noted, exist as a racemicmixture. Those molecules with two or more chiral centers, unlessotherwise noted, exist as a racemic mixture of diastereomers. Singleenantiomers/diastereomers may be obtained by methods known to thoseskilled in the art.

Where HPLC chromatography is referred to in the preparations andexamples below, the general conditions used, unless otherwise indicated,are as follows. The column used is a ZORBAX□ RXC18 column (manufacturedby Hewlett Packard) of 150 mm distance and 4.6 mm interior diameter. Thesamples are run on a Hewlett Packard-1100 system. A gradient solventmethod is used running 100 percent ammonium acetate/acetic acid buffer(0.2 M) to 100 percent acetonitrile over 10 minutes. The system thenproceeds on a wash cycle with 100 percent acetonitrile for 1.5 minutesand then 100 percent buffer solution for 3 minutes. The flow rate overthis period is a constant 3 ml/minute.

In the following examples and preparations, “Et” means ethyl, “Ac” meansacetyl, “Me” means methyl, and “Bu” means butyl.

EXAMPLES General Methods Preparation of 5-nitro-oxindole

To a solution of oxindole (26 g) in 100 mL of concentrated sulfuric acidat −15° C. was added fuming nitric acid (8.4 mL) dropwise. Carefulattention was paid to maintain the reaction temperature at −15° C. Afterthe addition was complete, the reaction was stirred for 30 minutes andthen poured into ice water. A yellow precipitate was formed which wasisolated by filtration to provide 34 grams (98%) of 5-nitro oxindole.

Preparation of 5-amino-oxindole (2)

To a solution of 5-nitro-oxindole (25 g) in 120 mL of dimethylacetamidein a Parr bottle was added 10% Pd/C (0.5 g). The mixture washydrogenated (40 psi H2) for 16 h. The catalyst was removed byfiltration and the filtrate was diluted with ether (2 L) to provide5-amino-oxindole (10.5 g; 50%).

Preparation of 2,4-dichloro-5-trifluoromethylpyrimidine (3)

5-Trifluoromethyluracil (250 g, 1.39 mol) and phosphorous oxychloride(655 mL, 6.94 mol, 5 equiv) were charged to a 3 L 4-neck flask equippedwith overhead stirrer, a reflux condenser, an addition funnel and aninternal theromocouple. The contents were maintained under a nitrogenatmosphere as concentrated phosphoric acid (85 wt %, 9.5 mL, 0.1 equiv)was added in one portion to the slurry, resulting in a moderateexotherm. Diisopropylethylamine (245 mL, 1.39 mol, 1 equiv) was thenadded dropwise over 15 min at such a rate that the internal temperatureof the reaction reached 85-90° C. by the end of the addition. By the endof the amine addition the reaction mixture was a homogenous light-orangesolution. Heating was initiated and the orange solution was maintainedat 100° C. for 20 h, at which time HPLC analysis of the reaction mixtureindicated that the starting material was consumed. External heating wasremoved and the contents of the flask were cooled to 40° C. and thenadded dropwise to a cooled mixture of 3N HCl (5 L, 10 equiv) and diethylether (2 L) keeping the temperature of the quench pot between 10 and 15°C. The layers were separated, and the aqueous layer was extracted oncewith ether (1 L). The combined organic layers were combined, washed withwater until the washes were neutral (5×1.5 L washes), dried with MgSO₄and concentrated to provide 288 g (95% yield) of a light yellow-orangeoil of 96% purity (HPLC). This material can be further purified bydistillation (bp 109° C. at 79 mmHg).

Preparation of5-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one(4)

To a solution of 5-trifluoromethyl-2,4-dichloropyrimidine (214.8 g;0.921 mol) in 1:1 DCE/tBuOH (1.240 L) was added Zinc chloride 1Msolution in ether (1 eq; 0.921 L). After 0.5 hour, 5-amino-oxindole (124g; 0.837 mol) was added followed by triethylamine (129.4 ml; 0.921 mol)keeping temperature at 25° C. The reaction was allowed to stir at roomtemperature overnight, then was concentrated and the product trituratedfrom methanol as a yellow solid (224.3 g; 82%). ¹H NMR (DMSO-d₆, 400MHz) δ 3.29 (s, 2H), 6.76 (d, J=7.9 Hz, 2H), 7.39 (d, J=8.3 Hz), 7.51(br s, 1H), 8.71 (s, 1H), 10.33 (s, 1H), 10.49 (s, 1H). ¹³C NMR(DMSO-d₆, 100 MHz) δ 177.0, 161.3, 158.7 (br), 140.7, 132.8, 126.9,123.7 (q, J=268 Hz), 121.0, 118.7, 111.2 (q, J=32 Hz), 109.6, 36.7; HPLCret. time: 5.759 min. LRMS (M+) 329.1, 331.1.

Example 15-[4-(R-1-Phenyl-ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one

To a solution of 1:1 DCE/t-BuOH alcohol (1:1 ratio, 4 mL) and5-(4-Chloro-5-trifluoromethyl-pyrimdin-2-ylamino)-1,3-dihydro-indol-2-one(0.15 g; 0.456 mmole) was added (R)(+) alpha phenethyl amine (0.071 mL;0.547 mmole) and diisopropyl ethyl amine (0.081 mL, 0.456 mmole). Theresultant solution was stirred under nitrogen and heated to 80° C. for16 hours. The reaction was cooled to room temperature, diluted with ˜10mL of a 1:1 mixture of dichloromethane and methanol followed by theaddition of 0.5 g of MP-carbonate. The resultant mixture was stirred,filtered, concentrated and purified by silica gel chromatography(97:2.8:0.3 ratio of chloroform/methanol/concentrated ammoniumhydroxide). The desired title compounds was obtained as a white solid(0.021 g; 11%). HPLC ret. time: 6.46 min. LRMS (M+) 413.4

The following compounds of the invention were prepared by heatingchloropyrimidine (4) with an appropriate amine as in Example 1. Aminesused in these reactions were either obtained commercially and used asreceived or alternatively they were prepared by common synthetic methodsfor amines known to those skilled in the art. Unless otherwise noted,compounds having chiral centers were prepared as racemic mixtures.

TABLE 1 Compounds Prepared by the Method of Example 1: HPLC MS RetentionData Time (M + Compound Name (min.) H)N-(1-Methyl-1-phenyl-ethyl)-3-{[2-(2-oxo- 6.46 597.52,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}- benzenesulfonamide3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.87 479.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzenesulfonamide 5-{4-[3-(Trifluoro-methanesulfonyl)- 6.35532.1 benzylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(Piperidin-3-ylmethyl)-amino]-5-3.74 407.3 trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(1-Methanesulfonyl-piperidin-3- 5.21 485.2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one N-(3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-5.22 493.3 ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide 3-Oxo-3-(3-{[2-(2-oxo-2,3-dihydro-1H-4.92 474.3 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-piperidin-1-yl)-propionitrile5-{4-[3-(1,1-Dioxo-1N⁶-isothiazolidin-2- 4.89 471.1yl)-propylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(2-Methyl-butylamino)-5- 6.53380.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(1-Methanesulfonyl-piperidin-2- 5.17 485.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one N-{2-[2-(2-Oxo-2,3-dihydro-1H-indol-5-4.38 431.2 ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide N-{4-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.78459.3 ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-butyl}-methanesulfonamide 5-{4-[(1-Methanesulfonyl-piperidin-4- 5.22485.3 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-4.81 445.1 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide Methanesulfonic acid3-{[2-(2-oxo-2,3- 5.67 494.1dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl esterN-{3-[2-(2-Oxo-2,3-dihydro-1H-indol-5- 4.58 445.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide 5-{4-[(4-Methanesulfonyl-morpholin-2- 4.87487.2 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-oneN-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H- 5.29 511.1indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide5-{4-[(5-Oxo-morpholin-2-ylmethyl)- 4.12 423.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-oneN-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro- 5.38 523.21H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-(4-Methyl-3-{[2-(2-oxo-2,3-dihydro-1H- 5.30 507.2indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide5-[4-(3-Methanesulfonylmethyl- 5.14 492.2benzylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-{4-[(4-Trifluoroacetyl-morpholin-2-5.64 505.1 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(1-Methanesulfonyl-azetidin-3-4.76 457.2 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one N-Methyl-N-(4-methyl-3-{[2-(2-oxo-2,3-6.66 521.3 dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)- methanesulfonamide5-{4-[(1-Methanesulfonyl-pyrrolidin-3- 4.97 471.2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-5.02 459.2 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide5-{4-[2-(1-Methanesulfonyl-piperidin-2-yl)- 5.71 499.4ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(4-Methanesulfonyl-pyridin-2-4.68 479.1 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one{2,2-Dimethyl-3-[2-(2-oxo-2,3-dihydro-1H- 7.01 495.0indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-carbamic acid tert-butyl ester5-[4-(3-Isopropoxy-propylamino)-5- 6.27 410.4trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(1-Methyl-piperidin-3-ylmethyl)- 3.71 421.0amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-{4-[(Tetrahydro-pyran-4-ylmethyl)- 5.16 408.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-[4-(2-Ethyl-butylamino)-5- 6.95 394.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(Tetrahydro-furan-2R-ylmethyl)- 5.30 394.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-{4-[(Tetrahydro-furan-2S-ylmethyl)- 5.30 394.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-{4-[(5-Methyl-furan-2-ylmethyl)-amino]- 5.98 404.25-trifluoromethyl-pyrimidin-2-ylamino}-1,3- dihydro-indol-2-one5-{4-[(1-Methanesulfonyl-pyrrolidin-2- 5.08 471.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(Adamantan-2-ylmethyl)-amino]-5-7.89 458.3 trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(Adamantan-2-ylmethyl)-amino]-5- 5.20 473.3trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-[4-(2-Methoxy-2-methyl-propylamino)-5- 5.87 396.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(endo-Bicyclo[2.2.1]hept-5-en-2- 6.74 416.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one (3-{[2-(2-Oxo-2,3-dihydro-1H-indol-5-5.03 522.2 ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-benzyl)-phosphonic acid dimethyl ester5-[4-(3-Methyl-butylamino)-5- 6.87 380.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(2-Hydroxy-cyclohexylmethyl)- 6.66 422.2amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-oneN-(4-Methoxy-3-{[2-(2-oxo-2,3-dihydro- 5.69 537.21H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl- methanesulfonamide5-{4-[(4-Ethanesulfonyl-morpholin-2- 5.11 501.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-(4-{[4-(Propane-2-sulfonyl)-morpholin-2- 5.35 515.2ylmethyl]-amino}-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one 5-{4-[(4-Acetyl-morpholin-2-ylmethyl)-4.43 451.2 amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(4-Propionyl-morpholin-2-ylmethyl)- 4.74465.2 amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-(4-{[4-(2,2-Dimethyl-propionyl)- 5.43 493.2morpholin-2-ylmethyl]-amino}-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one2-{[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.04 467.2ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-morpholine-4-carboxylic acid methyl ester5-{4-[(4-Methoxyacetyl-morpholin-2- 4.44 481.2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(3-Ethanesulfonyl-benzylamino)-5-5.36 492.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(4-Methanesulfonyl-morpholin-2R- 4.84 487.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(4-Methanesulfonyl-morpholin-2S-4.86 487.3 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(Pyrimidin-2-ylmethyl)-amino]-5-4.53 402.3 trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(Pyrazin-2-ylmethyl)-amino]-5- 4.42 402.1trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-oneN-(4-Fluoro-3-{[2-(2-oxo-2,3-dihydro-1H- 5.55 523.3indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-N-methyl- methanesulfonamide5-{4-[(1-Methanesulfonyl-piperidin-3- 5.17 485.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[(4-Isobutyryl-morpholin-2-ylmethyl)-amino]- 5.03 479.25-trifluoromethyl-pyrimidin-2-ylamino}-1,3- dihydro-indol-2-one5-[4-(3,3-Dimethyl-2-oxo-butylamino)-5- 6.00 408.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1,2-Dimethyl-propylamino)-5- 6.65 380.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(2-Methoxy-1-methyl-ethylamino)-5- 5.57 382.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[2-(1,1-Dioxo-1D⁶-isothiazolidin-2- 4.59 457.3yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(3-Methylamino-propylamino)-5-3.47 381.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(Pyridin-3-ylmethyl)-amino]-5- 4.62 401.3trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(6-Methanesulfonyl-pyridin-2- 4.89 479.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[3-(1,1-Dioxo-1,1,6-isothiazolidin-2- 5.45 519.2yl)-benzylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(1R-Phenyl-ethylamino)-5- 6.42414.4 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-(4-Isopropylamino-5-trifluoromethyl- 5.84 352.2pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-(4R-sec-Butylamino-5-trifluoromethyl- 6.22 366.2pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-(4S-sec-Butylamino-5-trifluoromethyl- 6.23 366.2pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(2-Methylamino-ethylamino)-5- 3.29 367.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1S-Phenyl-ethylamino)-5- 6.42 414.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(2-Methanesulfonylmethyl-thiazol-4- 4.72 499.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-(4-Propylamino-5-trifluoromethyl-5.91 352.2 pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(2-Hydroxy-1-methyl-ethylamino)-5- 4.49 368.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1-Hydroxymethyl-propylamino)-5- 4.85 382.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(5-Methanesulfonyl-pyridin-3- 4.55 479.4ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(Pyridin-4-ylmethyl)-amino]-5-4.49 401.2 trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-[4-(1,3-Dimethyl-butylamino)-5- 6.99 394.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-oneN-Isopropyl-N-{3-[2-(2-oxo-2,3-dihydro- 5.12 487.31H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide 5-[4-(1S-Hydroxymethyl-2-methyl-5.23 396.3 propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-oneN-Cyclohexyl-N-{3-[2-(2-oxo-2,3-dihydro- 6.24 527.21H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide5-[4-(1,2,3,4-Tetrahydro-naphthalen-1- 440.4 7.17ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]- 1,3-dihydro-indol-2-one5-{4-[(1-Methanesulfonyl-pyrrolidin-2S- 5.07 471.2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(3-Methyl-thiophen-2-ylmethyl)-6.18 420.4 amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(1-Methanesulfonyl-pyrrolidin-3R- 4.95471.2 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-[4-(2-Hydroxy-1S-phenyl-ethylamino)-5- 5.28 430.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(2-Hydroxy-1S-methyl-ethylamino)-5- 4.49 368.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1R-Hydroxymethyl-propylamino)-5- 4.85 382.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1-Pyrimidin-4-yl-ethylamino)-5- 4.84 416.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1,1-Dioxo-tetrahydro-1-thiophen-3- 4.67 426.3ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]- 1,3-dihydro-indol-2-one5-{4-[(1H-Imidazol-2-ylmethyl)-amino]-5- 3.27 390.3trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-[4-(2-Piperidin-2-yl-ethylamino)-5- 3.79 421.4trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(Isobutyl-methyl-amino)-5- 6.82 380.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-oneN-Methyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H- 5.49 507.4indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Ethyl-N-(3-{[2-(2-oxo-2,3-dihydro-1H- 5.67 521.3indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide5-[4-(2-Methanesulfonyl-benzylamino)-5- 5.47 478.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-oneN-Isopropyl-N-(3-{[2-(2-oxo-2,3-dihydro- 5.81 535.31H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide5-{4-[(3,4,5,6-Tetrahydro-2H- 5.79 484.3[1,2′]bipyridinyl-3-ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(1-Pyrimidin-2-yl-piperidin-3- 6.17 485.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[2R-(1-Methanesulfonyl-piperidin-2- 5.70 499.4yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[2S-(1-Methanesulfonyl-piperidin-2- 5.70 499.4yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(3-Methylsulfanyl-propylamino)-5-5.83 398.2 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1S-Hydroxymethyl-3-methylsulfanyl- 5.02 428.2propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one5-[4-(2-Hydroxy-1R-methyl-ethylamino)-5- 4.49 368.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1R-Hydroxymethyl-2-methyl- 5.23 396.4propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one N-Ethyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-5.31 473.3 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-methanesulfonamide5-{4-[(1-Methanesulfonyl-pyrrolidin-3R- 4.94 471.4ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(1S-Hydroxymethyl-propylamino)-5-4.86 382.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(3,5-Dinitro-benzylamino)-5- 6.04 490.1trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-oneN-(2-{[2-(2-Oxo-2,3-dihydro-1H-indol-5- 5.84 493.1ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamideN-Isopropyl-N-{2-[2-(2-oxo-2,3-dihydro- 5.37 473.31H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide5-[4-(2-Hydroxy-1-phenyl-ethylamino)-5- 5.29 430.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1R-Hydroxymethyl-3-methyl- 5.59 410.4butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-[4-(1S-Hydroxymethyl-3-methyl- 5.59410.4 butylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-{4-[(1-Methanesulfonyl-piperidin-2S-5.16 485.3 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(1-Methanesulfonyl-pyrrolidin-2R-5.08 471.3 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-[4-(Methyl-pyridin-2-ylmethyl-amino)-5- 5.37 415.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(3-Methanesulfonyl-benzyl)-methyl- 5.66 492.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-oneN-Methyl-N-(2-{[2-(2-oxo-2,3-dihydro-1H- 5.63 507.3indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-methyl}-phenyl)-methanesulfonamide5-[4-(Methyl-pyridin-3-ylmethyl-amino)-5- 5.25 415.4trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(1-Methanesulfonyl-piperidin-3- 5.69 499.4ylmethyl)-methyl-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-[4-(Methyl-pyridin-4-ylmethyl-amino)-5- 5.12 415.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-(4-Cyclopentylamino-5-trifluoromethyl- 6.47 378.3pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(2,6-Dimethoxy-benzylamino)-5- 6.78 460.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(1,5-Dimethyl-1H-pyrazol-3- 4.99 418.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(2-Imidazol-1-yl-ethylamino)-5-3.58 404.2 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(Pyridin-2-ylmethyl)-amino]-5- 4.95 401.4trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-[5-Trifluoromethyl-4-(2-trifluoromethyl- 6.57 468.2benzylamino)-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(3-Methyl-pyridin-2-ylmethyl)- 6.07 415.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-[4-(3-Methanesulfonyl-benzylamino)-5- 5.16 478.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[2-(1-Acetyl-piperidin-2-yl)- 5.22 463.4ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(1-Propionyl-piperidin-2-yl)-5.65 477.4 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[2-(1-Cyclopropanecarbonyl-piperidin- 5.86 489.42-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(1-Isobutyryl-piperidin-2-yl)-6.07 491.3 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(1-Butyryl-piperidin-2-yl)-5.99 491.4 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[2-(1-Methoxyacetyl-piperidin-2-yl)- 5.19 493.4ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[2-(1-Cyclobutanecarbonyl-piperidin- 6.31 503.42-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-4.47 423.3 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-acetamide N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H- 4.89437.45 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-propionamide Cyclopropanecarboxylic acid methyl-{3-[2-5.07 449.3 (2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- amideN-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H- 5.24 451.3indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-isobutyramide N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-5.25 451.4 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-butyramide 2-Methoxy-N-methyl-N-{3-[2-(2-oxo-2,3- 4.47453.3 dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-acetamide Cyclobutanecarboxylic acidmethyl-{3-[2- 5.48 463.4 (2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- amide2,2,N-Trimethyl-N-{3-[2-(2-oxo-2,3- 5.80 465.3dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-propionamide2,N-Dimethyl-N-{3-[2-(2-oxo-2,3-dihydro- 5.55 465.31H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-butyramide N-Methyl-N-{3-[2-(2-oxo-2,3-dihydro-1H-5.38 485.3 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-benzamide Isoxazole-5-carboxylic acid methyl-{3-[2-4.91 476.2 (2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- amideMorpholine-4-carboxylic acid methyl-{3-[2- 4.78 494.3(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- amide Ethanesulfonic acidmethyl-{3-[2-(2-oxo- 5.29 473.3 2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- amide Propane-1-sulfonicacid methyl-{3-[2-(2- 5.71 487.3 oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- amide1,1,3-Trimethyl-3-{3-[2-(2-oxo-2,3- 5.53 488.3dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}-sulfonylurea2,2,2-Trifluoro-N-methyl-N-{3-[2-(2-oxo- 5.80 477.22,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-propyl}- acetamideN-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H- 4.23 409.2indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-acetamide N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H- 4.61423.2 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-propionamide Cyclopropanecarboxylic acid methyl-{2-[2-4.77 435.2 (2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-amideN-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H- 4.94 437.2indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-isobutyramide N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-4.95 437.2 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-butyramide 2-Methoxy-N-methyl-N-{2-[2-(2-oxo-2,3- 4.21439.2 dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-acetamide Cyclobutanecarboxylic acidmethyl-{2-[2- 5.17 449.3 (2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-amide2,2,N-Trimethyl-N-{2-[2-(2-oxo-2,3- 5.57 451.4dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-propionamide2,N-Dimethyl-N-{2-[2-(2-oxo-2,3-dihydro- 5.26 451.41H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-butyramide N-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H-4.80 471.3 indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-benzamide Isoxazole-5-carboxylic acid methyl-{2-[2- 4.51462.3 (2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-amideMorpholine-4-carboxylic acid methyl-{2-[2- 4.41 480.3(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-amideN-Methyl-N-{2-[2-(2-oxo-2,3-dihydro-1H- 4.77 445.1indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-methanesulfonamide Ethanesulfonic acidmethyl-{2-[2-(2-oxo- 5.03 459.2 2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-amide Propane-1-sulfonicacid methyl-{2-[2-(2- 5.44 473.3 oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-amide1,1,3-Trimethyl-3-{2-[2-(2-oxo-2,3- 5.49 474.2dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}-sulfonylurea2,2,2-Trifluoro-N-methyl-N-{2-[2-(2-oxo- 5.49 463.22,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]-ethyl}- acetamide5-[4-(2-Hydroxy-ethylamino)-5- 4.05 354.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-(4-Cyclopropylamino-5-trifluoromethyl- 5.41 350.3pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-(4-Cyclobutylamino-5-trifluoromethyl- 6.01 364.3pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(1,4-Dimethyl-pentylamino)-5- 7.45 408.4trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(3-Imidazol-1-yl-propylamino)-5- 3.77 418.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(2-Phenoxy-ethylamino)-5- 6.34 430.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1-Cyclohexyl-ethylamino)-5- 7.61 420.4trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(1-Hydroxymethyl-2,2-dimethyl- 5.64 410.4propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-[4-(1-Methoxymethyl-propylamino)-5-5.96 396.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(Indan-2-ylamino)-5-trifluoromethyl- 6.78 426.4pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one5-[4-(1,2,3,4-Tetrahydro-naphthalen-1- 7.16 440.3ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]- 1,3-dihydro-indol-2-one5-(4-Cycloheptylamino-5-trifluoromethyl- 7.21 406.3pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-{4-[2-(2-Oxo-imidazolidin-1-yl)- 4.04 422.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 4-[2-(2-Oxo-2,3-dihydro-1H-indol-5-5.65 424.2 ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]- butyric acidethyl ester 5-[4-(2-Hydroxy-1-hydroxymethyl- 3.72 384.2ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-[4-(3-Hydroxy-2,2-dimethyl- 5.09396.3 propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-{4-[(Isochroman-1-ylmethyl)-amino]-5-6.36 456.3 trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-[4-(4-Hydroxy-1,1-dioxo-tetrahydro-1&- 4.42 442.2thiophen-3-ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one5-[4-(2-Methoxy-1-methyl-ethylamino)-5- 5.58 382.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(trans-4-Methylsulfanyl-tetrahydro- 5.37 426.3furan-3-ylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-{4-[trans-2-(Pyrimidin-2-ylsulfanyl)-6.32 488.3 cyclopentylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-[4-(Indan-1-ylamino)-5-trifluoromethyl- 6.86 426.3pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one5-{4-[2-(2-Hydroxy-ethylsulfanyl)- 4.66 414.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[2-(Pyridin-3-yloxy)-propylamino]-5- 5.20 445.3trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[2-(6-Methyl-pyridin-2-yl)- 5.00 429.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(2,3-Dihydro-benzo[1,4]dioxin-2-5.01 458.2 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(1-Methyl-1H-pyrazol-4-ylmethyl)-4.60 404.3 amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(4,5,6,7-Tetrahydro-benzothiazol-2- 5.93461.2 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(1-Phenyl-3-[1,2,4]triazol-1-yl-5.24 495.2 propylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 5-(4-Isobutylamino-5-trifluoromethyl-6.12 366.4 pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(2-Cyclohexyl-1-hydroxymethyl- 6.41 450.4ethylamino)-5-trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one 2-[2-(2-Oxo-2,3-dihydro-1H-indol-5-5.26 396.3 ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino]- propionicacid methyl ester 5-(4-Cyclohexylamino-5-trifluoromethyl- 6.82 392.3pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(3-Hydroxy-propylamino)-5- 4.24 368.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[2-(4-Methyl-1H-imidazol-2-yl)- 3.54 418.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(Tetrahydro-furan-3-ylamino)-5-4.89 380.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(Dicyclopropylmethyl-amino)-5- 6.59 404.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[2-(5-Methyl-4H-[1,2,4]triazol-3-yl)- 4.00 419.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-[4-(2-Ethylsulfanyl-ethylamino)-5-5.99 398.3 trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-[4-(2-Phenoxy-propylamino)-5- 6.57 444.2trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-{4-[(1-Ethyl-5-oxo-pyrrolidin-3- 4.57 435.2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-(4-{[1-(2-Methoxy-ethyl)-5-oxo- 4.44465.2 pyrrolidin-3-ylmethyl]-amino}-5-trifluoromethyl-pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-[4-(Benzhydryl-amino)-5-trifluoromethyl- 7.26 476.2pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one5-{4-[2-(1-Methyl-1H-pyrazol-4-yl)- 4.90 418.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[(4-Methyl-1H-imidazol-2-ylmethyl)- 3.40 404.2amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-{4-[(5-Cyclopropyl-1H-pyrazol-3- 5.00 430.2ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(4-Methyl-thiazol-5-yl)- 5.18435.2 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(1H-Benzoimidazol-2-yl)- 4.39454.2 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(5-Methyl-[1,3,4]oxadiazol-2-4.25 406.3 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(5-Phenyl-4H-[1,2,4]triazol-3-4.92 467.3 ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[(1H-Indol-2-ylmethyl)-amino]-5-6.10 439.3 trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(1,5-Dimethyl-1H-pyrazol-4- 4.77 418.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[(Benzothiazol-2-ylmethyl)-amino]-5- 5.77 457.2trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro- indol-2-one5-{4-[(3-Methyl-isoxazol-5-ylmethyl)- 5.02 405.3amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-{4-[(4-Methyl-thiazol-2-ylmethyl)- 5.12 421.2amino]-5-trifluoromethyl-pyrimidin-2-ylamino}- 1,3-dihydro-indol-2-one5-{4-[1-(4-Methyl-thiazol-2-yl)- 5.62 435.2ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{5-Trifluoromethyl-4-[(1,3,5-trimethyl- 4.95 432.21H-pyrazol-4-ylmethyl)-amino]-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[1-(2-Methyl-thiazol-4-yl)- 5.69435.3 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[(3-Methyl-imidazo[2,1-b]thiazol-6- 5.03 460.3ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-{4-[1-(5-Methyl-4H-[1,2,4]triazol-3-yl)- 4.20 419.3ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[1-(3,5-Dimethyl-1H-pyrazol-4-yl)-5.02 432.3 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)-4.85 432.4 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(4,6-Dimethyl-pyrimidin-2-yl)-5.17 444.4 ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one 5-{4-[2-(4-Methyl-5,6,7,8-tetrahydro-5.88 484.4 quinazolin-2-yl)-ethylamino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-[4-(2-Thiazol-4-yl-ethylamino)-5- 5.18 421.3trifluoromethyl-pyrimidin-2-ylamino]-1,3-dihydro- indol-2-one5-(4-Dimethylamino-5-trifluoromethyl- 5.60 338.3pyrimidin-2-ylamino)-1,3-dihydro-indol-2-one5-{4-[(1-Pyrimidin-2-yl-piperidin-3- 6.17 485.4ylmethyl)-amino]-5-trifluoromethyl-pyrimidin-2-ylamino}-1,3-dihydro-indol-2-one5-[4-(Indan-1-ylamino)-5-trifluoromethyl- 6.85 426.3pyrimidin-2-ylamino]-1,3-dihydro-indol-2-one

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

All patents, applications, publications, test methods, literature, andother materials cited herein are hereby incorporated herein by referencein their entireties.

1. (canceled)
 2. A compound of the formula I

or a pharmaceutically acceptable thereof, wherein n is 1; R¹ is asubstituent independently selected from the group consisting ofhydrogen, hydroxy, and —(C₁-C₆)alkyl optionally substituted by one tothree moieties independently selected from the group consisting ofhydrogen, halogen, hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵R⁶, —OR⁵,C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶ and —CONR⁵R⁸; R² is a substituentindependently selected from the group consisting of hydrogen and—(C₁-C₆)alkyl, optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —NO₂, —CN, —(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl,—C═N—OH, —C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl R² moieties may be optionallysubstituted by one to three R⁵ groups; R³ is (C₁-C₉)heteroaryl,optionally substituted by one to three moieties independently selectedfrom the group consisting of halogen, hydroxy, —(C₁-C₆)alkyl,(C₃-C₁₀)cycloalkyl, —NHSO₂(C₁-C₆)alkyl, —NHSO₂(C₃-C₆)cycloalkyl,N((C₁-C₆)alkyl)(SO₂(C₁-C₆)alkyl),—N((C₁-C₆)alkyl)(SO₂(C₃-C₆)cycloalkyl), —O(C₁-C₆)alkyl,—O—SO₂(C₁-C₆)alkyl, SO₂(C₁-C₆)alkyl, —SO₂(C₃-C₆)cycloalkyl, SO₂NH₂,SO₂NH(C₁-C₆)alkyl, —SO₂NH(C₃-C₆)cycloalkyl, —SO₂N((C₁-C₆)alkyl)₂,—SO₂N((C₃-C₆)cycloalkyl)₂, and —SO₂NR⁵R⁶ R⁴ is a substituent selectedfrom the group consisting of hydrogen, (C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,and —(C₂-C₉)heterocyclyl; wherein said (C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,and (C₂-C₉)heterocyclyl R⁴ substituents are optionally substituted byone to three moieties independently selected from the group consistingof hydrogen, halogen, —(C₁-C₆)alkyl, —CN, —NR⁵ ₂, —OR⁵,—(C₃-C₇)Cycloalkyl, —(C₂-C₉)heterocyclyl, —CO₂R⁵, and —CONR⁵R⁸; with theproviso that a heteroatom of the foregoing R⁴ substituents may not bebound to an sp³ carbon atom bound to another heteroatom; and wherein R⁵and R⁸ of said —CONR⁵R⁸ group may be taken together with the atoms towhich they are attached to form a —(C₃-C₁₀)cycloalkyl or—(C₂-C₉)heterocyclyl; R⁵ and R⁶ are each substituents independentlyselected from the group consisting of hydrogen, —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and—(C₁-C₉)heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocycly I, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl R⁵ or R⁶substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,—CF₃, —CN, —(C₁-C₆)alkyl, —NH(C₁-C₆)alkyl, —NH(C₃-C₇)cycloalkyl,—NH(C₂-C₉)heterocyclyl, —NH(C₆-C₁₀)aryl, —NH(C₁-C₉)heteroary,—N((C₁-C₆)alkyl)₂, —N((C₃-C₇)cycloalkyl)₂, —N((C₂-C₉)heterocyclyl)₂,—N((C₆-C₁₀)aryl)₂, —N((C₁-C₉)heteroaryl)₂, —O(C₁-C₆)alkyl,—O(C₃-C₇)cycloalkyl, —O(C₂-C₉)heterocyclyl, —O(C₆-C₁₀)aryl,—O(C₁-C₉)heteroaryl, —(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocycly, —CO₂R⁷,—CONH₂, —CONHR⁷, and —CONR⁷R⁸; with the proviso that a heteroatom of theforegoing R⁵ or R⁶ substituents or moieties may not be bound to an sp³carbon atom bound to another heteroatom; and wherein R⁷ and R⁸ of said—CONR⁷R⁸ group may be taken together with the atoms to which they areattached to form a —C₁-C₉)heteroaryl; R⁵ and R⁶ may be taken togetherwith the atom(s) to which they are attached to form a cyclic group,—(C₃-C₁₀)cycloalkyl or —(C₂-C₉)heterocyclyl, wherein said cyclic groupis optionally substituted by one to three moieties selected from thegroup consisting of hydrogen, halogen, hydroxy, —CF₃, —NO₂, —CN,—(C₁-C₆)alkyl, —(C₂-C₆)alkenyl, —(C₂-C₆)alkynyl, —C═N—OH,—C═N—O((C₁-C₆)alkyl), —NR⁵R⁶, —OR⁵, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R⁵, —CONR⁵R⁶, —CONR⁵R⁸, —SR⁷, —SOR⁷, —SO₂R⁷,—SO₂NR⁵R⁶, —NHCOR⁵, —NR⁵CONR⁵R⁶, and —NR⁵SO₂R⁷, wherein said—(C₂-C₆)alkenyl and —(C₂-C₆)alkynyl moieties of said cyclic group may beoptionally substituted by one to three R⁷ groups, and said cyclic groupis optionally interrupted by one to three elements selected from thegroup consisting of —(C═O), —SO₂, —S—, —O—, —N—, —NH— and —NR⁵, with theproviso that any of the foregoing cyclic group moieties or elements maynot be bound to an sp3 carbon atom that is bound to another heteroatom;R⁷ is a substituent selected from the group consisting of —(C₁-C₆)alkyl,—(C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉)heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉) heteroaryl R⁷substituents are optionally substituted by one to three moietiesindependently selected from the group consisting of hydrogen, halogen,hydroxy, —CN, —(C₁-C₆)alkyl, —NR⁵ ₂, and —O(C₁-C₆)alkyl, with theproviso that a heteroatom of the foregoing R⁷ substituents or moietiesmay not be bound to an sp3 carbon atom bound to another heteroatom; R⁸is a substituent selected from the group consisting of hydrogen,—(C₁-C₆)alkyl, (C₃-C₇)cycloalkyl, —(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl,and —(C₁-C₉) heteroaryl; wherein said —(C₁-C₆)alkyl, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —(C₆-C₁₀)aryl, and —(C₁-C₉) heteroaryl R⁸ radicalsare optionally substituted by one to three moieties independentlyselected from the group consisting of hydrogen, halogen, hydroxy, —CN,—(C₁-C₆)alkyl, —NH₂, —NHR⁹, —NR⁹ ₂, OR⁹, —(C₃-C₇)cycloalkyl,—(C₂-C₉)heterocyclyl, —CO₂R¹⁰, —CONH₂, —CONHR¹⁰, and —CONR¹⁰R¹¹; withthe proviso that a heteroatom of the foregoing R⁸ substituents ormoieties may not be bound to an sp3 carbon atom bound to anotherheteroatom; and wherein R¹⁰ and R¹¹ of —CONR¹⁰R¹¹ may be taken togetherwith the atoms to which they are attached to form a—(C₂-C₉)heterocyclyl; R⁹ and R¹⁰ are each —(C₁-C₆)alkyl and may be takentogether with the atoms to which they are attached to form a—(C₂-C₉)heterocyclyl; and R¹¹ is hydrogen or —(C₁-C₆)alkyl. 3-33.(canceled)
 34. The compound of claim 2 wherein R⁴ is hydrogen.
 35. Thecompound of claim 2 wherein R⁵ and R⁶ are each substituentsindependently selected from the group consisting of hydrogen and—(C₁-C₆)alkyl. 36-42. (canceled)
 43. A method for the treatment ofcancer solid tumor in a mammal comprising administering to said mammalan amount of a compound of claim 2 that is effective in treating saidcancer solid tumor. 44-45. (canceled)
 46. A pharmaceutical compositioncomprising a compound of claim 2 and a pharmaceutically acceptablecarrier.
 47. The compound of claim 2 wherein R¹ is hydrogen.
 48. Thecompound of claim 2 wherein R² is hydrogen.